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The City of Lander has played a major role in the settlement and development of west-central Wyoming since the late 1860s. It is associated with several major frontier themes: the Great 19th Century Westward Migration, due to its close proximity to the Oregon Trail; military explorations and Indian relations in the formation of the Lander Cut-Off in 1859 and the Wind River Indian Reservation in 1868; the nearby South Pass mining boom; the establishment of major transportation and communication routes to serve the Wind River Reservation; the arrival of the railroad in 1906; cattle and sheep ranching; the early 20th century oil industry; and Lander's development into a major commercial center in the Lander Valley. Euro-American settlement had begun in the Lander Valley shortly after the discovery and development of significant gold deposits in the South Pass area in 1867.

The Lander commercial district grew from a post office and several businesses established as early as 1875. The district experienced several major building booms, progressing from log and wood frame buildings to more substantial two-story brick and stone masonry edifices with highly ornamental facades. The majority of the remaining commercial buildings within the district date from the late 1880s-early 1890s boom. Despite subsequent boom and bust periods brought on by the wildly fluctuating energy and ranching industries, Lander has endured as a stable commercial and social center for the Lander Valley.