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The original inhabitants of the San Joaquin Valley region were the Yokuts people and Miwok people, who engaged in trading with other Californian tribes of Native Americans including coastal peoples such as the Chumash of the Central California coast, with whom they are thought to have traded plant and animal products.

The first European to enter the San Joaquin Valley was Pedro Fages in 1772. The county of Fresno was formed in 1856 after the California Gold Rush. It was named for the abundant ash trees (Spanish: fresno) lining the San Joaquin River.

Millerton, then on the banks of the free-flowing San Joaquin River and close to Fort Miller, became the county seat after becoming a focal point for settlers. Other early county settlements included Firebaugh's Ferry, Scottsburg and Elkhorn Springs.

The San Joaquin River flooded on December 24, 1867, inundating Millerton. Some residents rebuilt, others moved. Flooding also destroyed the town of Scottsburg on the nearby Kings River that winter. Rebuilt on higher ground, Scottsburg was renamed Centerville.

In 1867, Anthony "McQueen" Easterby purchased land bounded by the present Chestnut, Belmont, Clovis and California avenues, that today is called the Sunnyside district. Unable to grow wheat for lack of water, he hired sheep man Moses J. Church in 1871 to create an irrigation system.^{[citation needed]} Building new canals and purchasing existing ditches, Church then formed the Fresno Canal and Irrigation Company, a predecessor of the Fresno Irrigation District.

In 1872, the Central Pacific Railroad established a station near Easterby's—by now a hugely productive wheat farm—for its new Southern Pacific line. Soon there was a store around the station and the store grew into the town of Fresno Station, later called Fresno. Many Millerton residents, drawn by the convenience of the railroad and worried about flooding, moved to the new community. Fresno became an incorporated city in 1885. By 1931 the Fresno Traction Company operated 47 streetcars over 49 miles of track.

In 1865, William Helm brought his sheep to Fresno county, which was then a vast space of open land. By 1877, Helm made Fresno his home with a five-acre tract of land at the corner of Fresno and R streets. Helm was the largest individual sheep grower in Fresno County. In carrying his wool to market at Stockton, he used three wagons, each drawn by ten mules, and spent twelve days in making the round trip.

Two years after the station was established, county residents voted to move the county seat from Millerton to Fresno. When the Friant Dam was completed in 1944, the site of Millerton became inundated by the waters of Millerton Lake. In extreme droughts, when the reservoir shrinks, ruins of the original county seat can still be observed.

In the nineteenth century, with so much wooden construction and in the absence of sophisticated firefighting resources, fires often ravaged American frontier towns. The greatest of Fresno's early-day fires, in 1882, destroyed an entire block of the city. Another devastating blaze struck in 1883.

In 1909, Fresno's first and oldest synagogue, Temple Beth Israel, was founded.

Fresno entered the ranks of the 100 most populous cities in the United States in 1960 with a population of 134,000. Thirty years later, in the 1990 census, it moved up to 47th place with 354,000, and in the census of 2000, it achieved 37th place with 428,000.

The Fresno Municipal Sanitary Landfill was the first modern landfill in the United States, and incorporated several important innovations to waste disposal, including trenching, compacting, and the daily covering of trash with dirt. It was opened in 1937 and closed in 1987. It is a National Historic Landmark as well as a Superfund site.

Before World War II, Fresno had many ethnic neighborhoods, including Little Armenia, German Town, Little Italy, and Chinatown. In 1940, the Census Bureau reported Fresno's population as 94.0% white, 3.3% black and 2.7% Asian. Chinatown was primarily a Japanese neighborhood and today Japanese-American businesses still remain. During 1942, Pinedale, in what is now North Fresno, was the site of the Pinedale Assembly Center, an interim facility for the relocation of Fresno area Japanese Americans to internment camps. The Fresno Fairgrounds were also utilized as an assembly center.

Row crops and orchards gave way to urban development particularly in the period after World War II; this transition was particularly vividly demonstrated in locations such as the Blackstone Avenue corridor.

In September 1958, Bank of America launched a new product called BankAmericard in Fresno. After a troubled gestation during which its creator resigned, BankAmericard went on to become the first successful credit card. This financial instrument was usable across a large number of merchants and also allowed cardholders to revolve a balance (earlier financial products could do one or the other but not both). In 1976, BankAmericard was renamed and spun off into a separate company known today as Visa Inc.

The dance style commonly known as popping evolved in Fresno in the 1970s.

In the 1970s, the city was the subject of a song, "Walking Into Fresno", written by Hall Of Fame guitarist Bill Aken and recorded by Bob Gallion of the "WWVA Jamboree" radio and television show in Wheeling, West Virginia. Aken, adopted by Mexican-American movie actress Lupe Mayorga, grew up in the neighboring town of Madera and his song chronicled the hardships faced by the migrant farm workers he saw as a child. Aken also made his first TV appearance playing guitar on the old country-western show at The Fresno Barn.

Fictional residents of the town were portrayed in a 1986 comedic miniseries titled "Fresno", featuring Carol Burnett, Dabney Coleman, Teri Garr and Charles Grodin, along with numerous other celebrities. The mini series was presented as a parody of the prime time soap operas popular in the 1980s.

In 1995, the Federal Bureau of Investigation's Operation Rezone sting resulted in several prominent Fresno and Clovis politicians being charged in connection with taking bribes in return for rezoning farmland for housing developments. Before the sting brought a halt to it, housing developers could buy farmland cheaply, pay off council members to have it rezoned, and make a large profit building and selling inexpensive housing. Sixteen people were eventually convicted as a result of the sting.

Fresno is the larger principal city of the Fresno-Madera CSA, a Combined Statistical Area that includes the Fresno (Fresno County) and Madera (Madera County) metropolitan areas, which had a combined population of 922,516 at the 2000 census.

The 2010 United States Census reported that Fresno had a population of 494,665. The population density was 4,404.5 people per square mile (1,700.6/km²). The racial makeup of Fresno was 245,306 (49.6%) White, 40,960 (8.3%) African American, 8,525 (1.7%) Native American, 62,528 (12.6%) Asian (3.6% Hmong, 1.7% Indian, 1.2% Filipino, 1.2% Laotian, 1.0% Thai, 0.8% Cambodian, 0.7% Chinese, 0.5% Japanese, 0.4% Vietnamese, 0.2% Korean), 849 (0.2%) Pacific Islander, 111,984 (22.6%) from other races, and 24,513 (5.0%) from two or more races. Hispanic or Latino of any race were 232,055 persons (46.9%). Among the Hispanic population, 42.7% of the total population are Mexican, 0.4% Salvadoran, and 0.4% Puerto Rican. Non-Hispanic Whites were 30.0% of the population in 2010, down from 72.6% in 1970.

The Census reported that 485,798 people (98.2% of the population) lived in households, 4,315 (0.9%) lived in non-institutionalized group quarters, and 4,552 (0.9%) were institutionalized.

There were 158,349 households, of which 68,511 (43.3%) had children under the age of 18 living in them, 69,284 (43.8%) were opposite-sex married couples living together, 30,547 (19.3%) had a female householder with no husband present, 11,698 (7.4%) had a male householder with no wife present. There were 12,843 (8.1%) unmarried opposite-sex partnerships, and 1,388 (0.9%) same-sex married couples or partnerships. 35,064 households (22.1%) were made up of individuals, and 12,344 (7.8%) had someone living alone who was 65 years of age or older. The average household size was 3.07. There were 111,529 families (70.4% of all households); the average family size was 3.62.

The age distribution of the population shows 148,823 people (30.1%) under the age of 18, 62,601 people (12.7%) aged 18 to 24, 135,076 people (27.3%) aged 25 to 44, 102,064 people (20.6%) aged 45 to 64, and 46,101 people (9.3%) who were 65 years of age or older. The median age was 29.3 years. For every 100 females, there were 96.7 males. For every 100 females age 18 and over, there were 93.5 males.

There were 171,288 housing units at an average density of 1,525.2 per square mile (588.9/km²), of which 158,349 were occupied, of which 77,757 (49.1%) were owner-occupied, and 80,592 (50.9%) were occupied by renters. The homeowner vacancy rate was 2.6%; the rental vacancy rate was 7.6%. 235,430 people (47.6% of the population) lived in owner-occupied housing units and 250,368 people (50.6%) lived in rental housing units.

As of the census of 2000, there were 427,652 people, 140,079 households, and 97,915 families residing in the city. The population density was 4,097.9 people per square mile (1,582.2/km²). There were 149,025 housing units at an average density of 1,427.9 square miles (3,698 km²). The racial makeup of the city was 50.2% White, 8.4% Black or African American, 1.6% Native American, 11.2% Asian (about a third of which is Hmong), 0.1% Pacific Islander, 23.4% from other races, and 5.2% from two or more races. Hispanic or Latino of any race were 39.9% of the population.

There were 140,079 households, of which 40.4% had children under the age of 18 living with them, 46.1% were married couples living together, 17.6% had a female householder with no husband present, and 30.1% were non-families. 23.3% of all households were made up of individuals, and 7.9% had someone living alone who was 65 years of age or older. The average household size was 2.99 and the average family size was 3.57.

In the city, the age distribution of the population shows 32.9% under the age of 18, 11.8% from 18 to 24, 28.8% from 25 to 44, 17.2% from 45 to 64, and 9.3% who were 65 years of age or older. The median age was 28 years. For every 100 females, there were 96.6 males. For every 100 females age 18 and over, there were 93.0 males.

The median income for a household in the city was $32,236, and the median income for a family was $35,892. Males had a median income of $32,279 versus $26,551 for females. The per capita income for the city was $15,010. About 20.5% of families and 26.2% of the population were below the poverty line, including 36.5% of those under age 18 and 10.7% of those age 65 or over.

The population as of July 1, 2007 was estimated to be 470,508 by the US Census Bureau's Population Estimates Program. The Fresno Metropolitan Statistical Area population was estimated at 899,348.

In 1920, Armenians comprised 9% of the population of the city of Fresno, with 4,000 Armenian residents at the time.Old Armenian Town was the old Armenian neighborhood in the center of Fresno. Famous author William Saroyan was born in Fresno in 1908.

The Fresno Hmong community, along with that of Minneapolis–Saint Paul, is one of the largest two urban U.S. ethnic Hmong communities, with just over 24,000 people, or about 5% of the city's population, being of Hmong descent.