Recent human history of the Rocky Mountains is one of more rapid change. The Spanish explorer Francisco Vásquez de Coronado—with a group of soldiers, missionaries, and African slaves—marched into the Rocky Mountain region from the south in 1540. The introduction of the horse, metal tools, rifles, new diseases, and different cultures profoundly changed the Native American cultures. Native American populations were extirpated from most of their historical ranges by disease, warfare, habitat loss (eradication of the bison), and continued assaults on their culture.

In 1739, French fur traders Pierre and Paul Mallet, while journeying through the Great Plains, discovered a range of mountains at the headwaters of the Platte River, which local American Indian tribes called the "Rockies", becoming the first Europeans to report on this uncharted mountain range.
Sir Alexander MacKenzie (1764–March 11, 1820) became the first European to cross the Rocky Mountains in 1793. He found the upper reaches of the Fraser River and reached the Pacific coast of what is now Canada on July 20 of that year, completing the first recorded transcontinental crossing of North America north of Mexico. He arrived at Bella Coola, British Columbia, where he first reached saltwater at South Bentinck Arm, an inlet of the Pacific Ocean.

The Lewis and Clark Expedition (1804–1806) was the first scientific reconnaissance of the Rocky Mountains. Specimens were collected for contemporary botanists, zoologists, and geologists. The expedition was said to have paved the way to (and through) the Rocky Mountains for European-Americans from the East, although Lewis and Clark met at least 11 European-American mountain men during their travels.

Mountain men, primarily French, Spanish, and British, roamed the Rocky Mountains from 1720 to 1800 seeking mineral deposits and furs. The fur-trading North West Company established Rocky Mountain House as a trading post in what is now the Rocky Mountain Foothills of present-day Alberta in 1799, and their business rivals the Hudson's Bay Company established Acton House nearby. These posts served as bases for most European activity in the Canadian Rockies in the early 19th century. Among the most notable are the expeditions of David Thompson (explorer), who followed the Columbia River to the Pacific Ocean. On his 1811 expedition, he camped at the junction of the Columbia River and the Snake River and erected a pole and notice claiming the area for the United Kingdom and stating the intention of the North West Company to build a fort at the site.

By the Anglo-American Convention of 1818, which established the 49th parallel north as the international boundary west from Lake of the Woods to the "Stony Mountains"; the UK and the USA agreed to what has since been described as "joint occupancy" of lands further west to the Pacific Ocean. Resolution of the territorial and treaty issues, the Oregon dispute, was deferred until a later time.

In 1819, Spain ceded their rights north of the 42nd Parallel to the United States, though these rights did not include possession and also included obligations to Britain and Russia concerning their claims in the same region.

After 1802, American fur traders and explorers ushered in the first widespread Caucasian presence in the Rockies south of the 49th parallel. The more famous of these include Americans William Henry Ashley, Jim Bridger, Kit Carson, John Colter, Thomas Fitzpatrick, Andrew Henry, and Jedediah Smith. On July 24, 1832, Benjamin Bonneville led the first wagon train across the Rocky Mountains by using South Pass in the present State of Wyoming. Similarly, in the wake of Mackenzie's 1793 expedition, fur trading posts were established west of the Northern Rockies in a region of the northern Interior Plateau of British Columbia which came to be known as New Caledonia, beginning with Fort McLeod (today's community of McLeod Lake) and Fort Fraser, but ultimately focused on Stuart Lake Post (today's Fort St. James).

Negotiations between the United Kingdom and the United States over the next few decades failed to settle upon a compromise boundary and the Oregon Dispute became important in geopolitical diplomacy between the British Empire and the new American Republic. In 1841 James Sinclair, Chief Factor of the Hudson's Bay Company, guided some 200 settlers from the Red River Colony west to bolster settlement around Fort Vancouver in an attempt to retain the Columbia District for Britain. The party crossed the Rockies into the Columbia Valley, a region of the Rocky Mountain Trench near present-day Radium Hot Springs, British Columbia, then traveled south. Despite such efforts, in 1846, Britain ceded all claim to Columbia District lands south of the 49th parallel to the United States; as resolution to the Oregon boundary dispute by the Oregon Treaty.
Thousands passed through the Rocky Mountains on the Oregon Trail beginning in the 1840s. The Mormons began to settle near the Great Salt Lake in 1847. From 1859 to 1864, gold was discovered in Colorado, Idaho, Montana, and British Columbia, sparking several gold rushes bringing thousands of prospectors and miners to explore every mountain and canyon and to create the Rocky Mountains' first major industry. The Idaho gold rush alone produced more gold than the California and Alaska gold rushes combined and was important in the financing of the Union Army during the American Civil War. The transcontinental railroad was completed in 1869, and Yellowstone National Park was established as the world's first national park in 1872. Meanwhile, a transcontinental railroad in Canada was originally promised in 1871. Though political complications pushed its completion to 1885, the Canadian Pacific Railway eventually followed the Kicking Horse and Rogers Passes to the Pacific Ocean. Canadian railway officials also convinced Parliament to set aside vast areas of the Canadian Rockies as Jasper, Banff, Yoho, and Waterton Lakes National Parks, laying the foundation for a tourism industry which thrives to this day. Glacier National Park (MT) was established with a similar relationship to tourism promotions by the Great Northern Railway. While settlers filled the valleys and mining towns, conservation and preservation ethics began to take hold. U.S. President Harrison established several forest reserves in the Rocky Mountains in 1891–1892. In 1905, U.S. President Theodore Roosevelt extended the Medicine Bow Forest Reserve to include the area now managed as Rocky Mountain National Park. Economic development began to center on mining, forestry, agriculture, and recreation, as well as on the service industries that support them. Tents and camps became ranches and farms, forts and train stations became towns, and some towns became cities.

European exploration
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Indigenous People