When the first Euro-Americans passed through in the 1840s, Washoe and Paiute peoples inhabited the land along the Truckee River. In the late 1840s and 1850s, thousands of travelers on their way to the California gold fields would linger a few days in the Truckee Meadows to feed their animals on the native grasses before crossing the Sierra Nevada. The meadows, fed by the river, offered an oasis, but to travelers, the river was also an obstacle.

In 1857, Charles Gates and John Stone attempted to build a bridge across the river, but spring floods, fed by snowmelt in the mountains, washed it away. In 1860, Charles Fuller built a bridge and a log shelter for travelers upstream from Stone and Gates, and the place became known as Fuller's Crossing. Around the same time, a gold discovery in the hills twenty miles south changed the direction of the gold rush of ten years earlier to what became known as the "Rush to Washoe." Movement in and around the region increased, suggesting the potential for increased demand on the Truckee River crossing.

In 1861, Myron C. Lake purchased Fuller's toll bridge. Lake continued to operate the hotel, which he renamed the Lake House, and developed other businesses to enhance his operation. With profits from his enterprise, Lake purchased additional land surrounding his bridge. Until the arrival of the railroad, the place was called Lake's Crossing.

The Central Pacific Railroad, which began construction in Sacramento in January 1863, reached Reno in May 1868. Its route through the Truckee Meadows followed the river. The location of the depot and a townsite in the Meadows was particularly important, as it was to be the last major stop before westward trains made their way over the steep and rugged Sierra Nevada. Myron Lake sold the railroad 160 acres for a depot and town—and Reno was born, establishing the theme of transportation that would dominate its development for many years.

Lots in the town site went up for auction on May 9, 1868. By mid-July, trains carrying everything from livestock to construction materials were running Monday through Saturday between Sacramento and Wadsworth. Casting itself as an upstart, Reno almost immediately set out to wrest the county seat from Washoe City. Following a struggle among railroad officials, local businessmen, and Myron Lake, Reno's courthouse was built on a parcel of Lake's land south of the river.

Reno managed to claim another plum state institution in 1884, when Nevada's land-grant university moved from Elko, in the eastern part of the state. Morrill Hall, the first building, was completed in 1885. The university brought the town the prestige it yearned for.

The products of the area's agriculture, particularly cattle and alfalfa hay, made constant demands on Reno's rail services, creating an immediate economic mainstay for the town. While Nevada mining entered an economic depression for the last two decades of the nineteenth century, Reno grew into the state's largest town.

As the nineteenth century drew to a close, Reno was the state's financial and industrial center, a bustling small metropolis with fashionable Victorian homes and consequential commercial and municipal buildings. However, it was still a dusty, raucous railroad town with commerce and characters befitting the Wild West. These opposing forces would continue to color Reno's image as the twentieth century dawned.

A mining boom in southern and central Nevada in the early 1900s gave Nevada another economic shot in the arm. Reno benefited from the new mining boom, both economically and through George Wingfield's arrival. From Reno, Wingfield ran his empire, which included such diversified endeavors (both legal and illegal) as politics, banking, and gambling. With the coming of the twentieth century, however, the spirit of the town, with a population of about 4,000, began to change. In 1903, Reno incorporated. In new construction, builders and architects concentrated on permanence and style, while culturally the town demonstrated its growing refinement through the Carnegie Library and the founding of the Nevada Historical Society in 1904. The town burst on the national scene in 1905 with the much-publicized divorce of U. S. Steel Corporation president William Corey. Once the country discovered the potential for the migratory divorce trade in Nevada, Reno became the divorce mecca of the world, a title it held for sixty years.

During this early period, Reno garnered the label, "Nevada's Sin City." Activities such as prostitution, gambling, prize fighting, quick marriages, and easy divorces brought to Reno a colorful array of people from all walks of life. Except for a brief time during the Progressive Era, Nevada discovered that when its traditional economic mainstays of mining and agriculture fell often to the vagaries of boom-and-bust, the legislation of sin filled the gap with remarkable dependability. When, in 1931, the Nevada legislature lowered the divorce residency period to six weeks and passed the Wide Open Gambling Law, Reno, then boasting a population of 18,500, was immediately thrust into the American consciousness as a destination where one could do things unthinkable at home. The rich and famous and average citizens came to buy what Reno was selling. Learning that it could profit from sin was a significant revelation for Nevada, since from the post-World War II years on, it has staked its economic livelihood on casino gaming and tourism, which developed and flourished on the heels of the divorce trade. Legal gambling, now a national institution, began in Reno as privately held—often mob-owned—gambling halls, but in the 1960s, Reno gambling started going corporate, and the gambling halls changed into large hotel-casinos.

While Reno projected a welcoming image as the Biggest Little City in the World, it struggled with social issues, particularly in the first half of the twentieth century. Racial discrimination prevented minorities from participating in activities enjoyed by the white population, and as a result the minority populations remained small. African-American institutions, such as Bethel A. M. E. Church, founded in 1907, provided services for minorities, from social events to housing and employment. Bethel members founded the first NAACP branch in Nevada in 1919. The few businesses that catered to minorities were located in the vicinity of Lake Street and Commercial Row.

Reno has always been a town of contrasts: cosmopolitan on the edge of the desert; the academy uphill from the gambling district; the darkness and despair of the human soul amid exquisite natural beauty. For decades, Reno was Nevada's economic, political, and population center until Las Vegas assumed that role in the 1960s. Despite the shift in the state's power base from north to south, during the latter half of the twentieth century Reno experienced phenomenal growth. With a 1960 population of 51,470, and a more diversified economy that included increased manufacturing, tax-exempt warehousing, a broadened tourism market, and the attraction of retirees from California, Reno faced the common problems of sprawl and the decline of the downtown core. Legislatively mandated regional planning and serial plans to revitalize downtown sought to address and manage these issues.

By the 2000 census, Washoe County was home to 339,486, with 180,480 residing within Reno's city limits. There have been significant changes in Reno during the first few years of the new century. The demolition of the iconic historic Mapes Hotel in 2000, the construction of a world-class kayak park in 2005, and the lowering of the railroad tracks through town, completed in 2006, have altered the downtown landscape. To handle the population growth, the City is annexing county land to support shopping centers, housing developments, and new schools. The University is expanding, as well, with two major construction projects to be completed in 2007 and 2008. Long after travelers welcomed and cursed the Truckee and the Sierra Nevada, and railroad-building inspired the first spurt of growth and development, Reno continues to serve tourists while forging its own identity as a community.