On November 30, 1803, the United States bought Louisiana from Napoleon. U.S. President Thomas Jefferson decided to send two explorers Meriwether Lewis and William Clark to discover this huge terra incognita.

Lewis & Clark is a board game where each player manages an expedition intended to cross the North American continent. Their aim is to be the first to reach the Pacific. Each one has their own Corps of Discovery that will be completed by the Native Americans and the trappers met during the journey. They have to cleverly manage their characters and also the resources they finds along the way. Beware, sometimes frugality is better than abundance.

Lewis & Clark contains dual use cards. To be activated, one card must be used with another one, which becomes unavailable for a while. Thus, players are then faced with a constant dilemma: play a card or sacrifice it. During the game, each player obtains character cards that enlarge his hand, building a crew that gives him more options but it needs to be optimized as he will recycle his cards more slowly. This new "handbuilding" mechanism fits strongly with the historical background.

Since the goal of the game is to be the first on the Pacific coast, the timing and the opportunistic use of the other players' positions are crucial.