Santa Fe is about western expansion of the railroads in the United States. Players build track for the five major railroads that are represented in the game: Great Northern, Union Pacific, Atchinson Topeka & Santa Fe, Kansas Pacific, and Southern Pacific.

Players gain points for connecting each new city on the map ad special bonus points for connecting cities which were key parts of the actual railroad lines. However, players will often disagree about the direction each railroad should take, since each player has interests in certain cities and no interest in others. So, it is the player who connects most railroads to the cities who will be the winner.