On April 7, 1805, the permanent party of the Lewis and Clark expedition set out up the Missouri River from Fort Mandan in present day North Dakota. They had spent the winter among the Mandan and Hidatsa Indians, waiting for the river's ice to break up and make travel possible. On the same day that they headed upriver, their keelboat which had brought them as far as the Mandan villages set off downriver for St. Louis with most of their French boatmen and a squad of soldiers under Corporal Richard Warfington. The boat carried dispatches and ethnological and natural history specimens which the captains were sending back to President Thomas Jefferson—the first fruits of the expedition.

The Corps of Discovery was now entering an area where there had been no previous white exploration, although they were informed about the country as far as the Continental Divide from the Mandans and Hidatsas. They also had with them the Shoshone woman Sacagawea, through whom they hoped to make friendly contact with her people living along the divide. Beyond that point they could only hope that with Indian assistance and guidance they could make a portage of the Rocky Mountains to some navigable stream flowing into the Columbia River, and thus reach the Pacific.

They would spend the rest of the spring and summer toiling their way up the Missouri to its headwaters in their two pirogues and six canoes. On April 25 Lewis with four men reached the Yellowstone River, near the present North Dakota-Montana boundary. Two days later, after taking astronomical readings to fix the position of the site, they passed on into Montana. The journey across Montana, unlike the earlier stages of the trip, brought no encounters with Indians. The party observed signs of Assiniboine and Blackfeet encampments, but the people themselves were absent. It may be, however, that Indians did observe the group's passage without making themselves known. In place of meetings with Indians, however, the party began a series of combats with grizzly bears. At first they had thought that their superior weaponry would give them an advantage over these animals—one not possessed by the Indians. Instead, the subsequent encounters led them to feel some of the same awe and respect for the bear that the Indians did.

Other natural phenomena posed even greater dangers. The severe spring winds sometimes made it impossible to navigate safely on the river, thus impeding their progress. On May 14 a pirogue turned on its side in a squall of wind, nearly causing the loss of its contents and passengers, including Sacagawea and her baby. Aside from the potential human tragedy, the loss of the supplies in the pirogue might have made it impossible for the expedition to continue; fortunately the quick action of boatman Pierre Cruzatte righted the craft and saved the situation.

As they moved west the country grew increasingly arid and rugged. Small mountain ranges in the distance came into view which the captains assumed to be part of the Rockies. To the north and south they were viewing the present Bears Paw, Little Rocky, and Judith mountains. In late May the travelers entered the Breaks of the Missouri, an area of colorful and impressive geological formations, including the fantastically sculpted White Cliffs, which prompted Lewis to pen a romantic description of these "seens of visionary enchantment." Clark named one major stream in the area for a young woman, Julia Hancock, who would later become his wife and today it retains that name, the Judith. The captains were also beginning to notice new species not seen on the lower Missouri. Ponderosa pine began to appear as did quaking aspen, sagebrush, and new varieties of willows and cottonwood trees. They were also taken with the abundance of currants and gooseberries. While the expedition's fisherman Silas Goodrich caught goldeye and cutthroat trout, others saw new animals such as the prairie rattlesnake, the Montana horned owl, and the thirteen-lined ground squirrel.

After nearly two months of travel, on June 2, the Corps arrived at the mouth of a major fork of the Missouri which they named the Marias River, after a cousin of Lewis's. This stream posed a dilemma, for none of the information given them by the Mandans and Hidatsas had referred to this stream. The problem was to determine which fork was the true Missouri, which would lead them to the Contiental Divide. To make the wrong decision and take the wrong river might cause such delay as to leave them stranded in the mountains in winter with the likelihood that the expedition would fail altogether. Matters were not helped by the fact that, while the captains believed that the river coming from the southwest was the Missouri, virtually all their men were sure that the other fork was the one to be followed. The captains led reconnaissances a short distance up each stream, without reaching any satisfactory conclusion. Finally they decided to set off up the southwest fork, with Lewis going ahead with a few men in the hope of finding an identifiable landmark soon enough to determine if they were in error.

On June 13 Lewis found the evidence that proved they were on the right river; the Hidatsas had told them of the Great Falls of the Missouri, the point at which the river emerged from the mountains. As his little group walked upstream, Lewis heard a roaring and saw clouds of spray that could only come from the falls. His relief was great, reflected in his ecstatic description of the beauty of the "sublime" spectacle, but the presence of the five cascades and intervening rapids presented a new problem, for the canoes and supplies must now be portaged around this obstacle. This task would consume an entire month of their precious time.

A survey of the area showed that a portage of about eighteen miles would be necessary to skirt the falls. To transport the heavy canoes and goods to their upper portage camp they constructed crude carriages out of cottonwood, the wheels being rounded slabs of the trunks. The men had to pull heavy loads across ground roughened by the dried tracks of buffalo and infested with prickly pear cactus, all of which tormented their moccasined feet. The exertion was so great that at every rest stop they fell down and went immediately to sleep. Some of the men were exempted from this labor to hunt for the party's food, but they had to contend with the numerous grizzly bears. Heavy rain showers drenched everyone, and large hailstones injured several. During one downpour Clark, surveying the falls with Charbonneau, Sacagawea, her baby, and York, was nearly swept into the Missouri by a flash flood coming down the gully in which the little group had taken refuge.

At the upper portage camp Lewis labored on a collapsible boat of his own design, whose dismantled frame the party had transported across the continent for use when heavier boats had to be left behind. The frame could be bolted together and covered with animal skins. Unfortunately, tar was required to make the invention waterproof, and there were no pine trees near the area to provide it. Attempts to contrive a substitute were unsuccessful; the boat leaked too badly to be useful. The captains decided that Clark should go ahead several miles upriver where there were some sizable cottonwood trees and build two more dugout canoes.

On July 15 the party set out from the canoe-building camp, after more than three months of travel from Fort Mandan. First Lewis and then Clark forged ahead of the main party looking for the Shoshones, for it was now vital to find these Indians to obtain horses and guides for the mountain crossing which increasingly appeared likely. The party moved through the deep canyon which they called "Gates of the Rocky Mountains," a name which remains today. They were now within the mountains, and shallow waters and rapids would make navigation increasingly difficult. On July 25 Clark with four men reached the Three Forks of the Missouri, of which the Hidatsas had told them. Lewis with the main party reached the forks two days later, and the captains decided to name the three streams the Jefferson, the Madison, and the Gallatin, after the president and his secretaries of state and treasury. There was still no contact with the Shoshones, although various signs of their presence were evident. Sacagawea was now recognizing familiar landmarks. A meeting with her people was now their most urgent concern.