Captain Lewis had the more dangerous assignment because his explorations took him to the lands of the feared Blackfoot and Gros Ventre Indians – warlike tribes already well known for attacking intruders in their territories.  The huge Blackfoot/Blackfeet nation had an estimated population of 16,000-20,000 divided among three allied Algonquian Piegan (Pikuni) and Blackfoot (Siksika).  They were traditional horse-riding, buffalo-hunting, and tipi-living people of the plains, who inhabited northwestern Montana and adjoining lands of southern Canada.

The nearest neighbors and closest allies of the Blackfoot were the Atsina or Gros Ventre (pronounced "grow vont" and meaning "big belly" in French).  In Lewis and Clark's day, they were usually called the "Minitarees of the North" or "Gros Ventres of the Prairies" to distinguish them from the Hidatsa ("Minitarees of the River").  Those names have always been confusing, for there was never any connection between those two very different Indian tribes.  The nomadic, Algonquian-speaking Atsina population was much smaller than the Blackfoot.  The tribe had once been combined with the Arapaho, which separated and moved south to ally with the Cheyenne, and the Atsina/Gros Ventre suffered additional loss of population in smallpox epidemics of the 1780s.

On Saturday, 26 July 1806, Lewis and his scouting party of Drouillard and the two Field brothers spotted eight Indians with some 30 horses along the south bank of Two Medicine River, near present-day Cut Bank, Montana. Lewis parleyed with these warriors, learning through sign language (indicating a fat gut) that they were Minitarees of the North – in other words, Gros Ventre or Atsina.  He handed them a Jefferson peace medal, a United States flag, and a handkerchief.  The two groups camped together that evening, and over several pipes of shared tobacco, Lewis told the Indians that he had "come a great way from the East up the large river which runs towards the setting sun" and "had seen a great many nations" on his journey "to the great waters where the sun sets."  The Indians fell asleep, while one American always stayed awake to prevent stealing.

Just after dawn on Sunday, 27 July, Lewis was awakened from a deep sleep by the shouting of the Field brothers.  Indians, who were now running away, had grabbed their two rifles and the two belonging to Lewis and Drouillard.  Reuben Fields caught up with the warrior wearing the peace medal and grabbed his rifle while stabbing the man in the heart.  Lewis ran after two other Indians and retrieved his rifle after threatening to shoot the thief with his pistol. 

The two warriors ran off and tried to scatter the Expedition's horses, when Lewis caught up with them and shot one of the Indians in the stomach.  Before dying, he fired back, and Lewis said that he could feel the wind from the bullet as it passed close to his head.  The Corpsmen returned to camp and burned four shields, two bows, two quivers full of arrows, and other articles left by the Indians.  Lewis reclaimed the U.S. flag but left the "peace and friendship" medal around the neck of the stabbed warrior so that his people "might be informed who we were."

Fearing that the escaped Indians would soon return with reinforcements, the Americans quickly collected and saddled their remaining horses, as well as four better ones left by the Indians, and rode away at full speed.  Lewis's party covered 63 miles by 3 pm, before resting.  They met up with other members of the Expedition the next day and continued their journey home by water.

The famous "Two Medicine River Fight" of 27 July resulted in the only Indian fatalities directly caused by the Corps of Discovery.  Until very recently, the Indians involved were always described as Blackfoot, but it is now clear that they were Atsina/Gros Ventre.  Historians have long claimed that this bloody skirmish was a major reason why the Blackfoot killed Drouillard and another Corpsman a few years later.