He played in Major League Baseball (MLB) for the Atlanta Braves, Kansas City Royals, Detroit Tigers, Cincinnati Reds and St. Louis Cardinals.

On May 28, 2006, he hit his first Major League home run, a seventh-inning solo shot off Roberto Novoa in a 13-12 Braves win.

[3] In 2010, he earned a spot in the big-league roster during spring training and spent the 2010 season backing up Jason Kendall.

On November 20, 2012, the Royals designated Peña for assignment as they made room on the 40-man roster ahead of the Rule 5 draft.

[9] By the 2014 all-star break, Peña was on his way to a career year, playing in 65 games and batting .250 with three home runs, 17 RBI and an already career-best 12 doubles.

On November 30, 2015, Peña agreed to a two-year, $5 million contract with the St. Louis Cardinals to be the primary backup to Yadier Molina.

[10] In mid-December 2015, Peña accompanied an expedition to Cuba composed of former Cardinals including Joe Torre and Jon Jay, and other MLB officials and players.

It was MLB's first visit there since 1999, and one anticipated as an important step to help normalize relations with the United States that had begun to ease earlier in the year.

[11][12] He began the season on the DL after surgery to remove loose cartilage in his left knee, which he attributed to slipping on the dugout steps in spring training.

[citation needed] On February 7, 2017, Peña signed a minor league contract with the Kansas City Royals that included an invitation to spring training.