Born in Ponce, Puerto Rico, Santiago came up to the major leagues in 1987 with the San Diego Padres and he established a Major League record that year for a rookie by hitting safely in 34 straight games. He won the National League's Rookie of the Year Award unanimously that year.
Santiago failed to match all the hype that subsequently followed him, and his hitting was not helped by his poor plate discipline. He joined the Marlins in 1993, who traded him to the Reds, where he briefly recovered his best form. Bouncing in 1996 to the Phillies (where he became the first player to hit a grand slam off Greg Maddux) and Blue Jays (1997-98), he lost almost the entire 1998 season to a serious injury sustained in a car crash in Florida. A free agent again, he played 89 games for the Cubs before arriving in San Francisco in 2001, where he has been able to put up decent numbers while helping his team to the playoffs in 2002. His good hitting continued in the playoffs, where he was named 2002 National League Championship Series MVP.
In 2003, Santiago was named by FBI investigators as one of the athletes alleged to have received anabolic steroids, via the Bay Area Laboratory Co-operative. In 2004, Santiago, again a free agent, signed with the Kansas City Royals. He began the season putting up decent numbers, but after sustaining injuries that sent him to the disabled list, the team began to start John Buck at the catcher position, making Santiago expendable. After the 2004 season, the Royals traded him to the Pittsburgh Pirates for Leo Nunez, a rookie pitcher. The Pirates dumped Santiago after a mere 23 at-bats when cheap acquisition David Ross turned out to be a much better defensive catcher. Santiago signed with the New York Mets to a AAA minor-league contract, but he appeared in only a handful of games.
With his career almost certainly over, discussions have arisen about where he ranks among the game's all-time catchers. His main claim to fame is his excellent durability, which has allowed him to post productive numbers late in his career, at an age when most catchers are already retired.