He played 20 seasons in Major League Baseball (MLB) for the San Diego Padres, Pittsburgh Pirates, New York Mets, Seattle Mariners, Arizona Diamondbacks, Houston Astros, Washington Nationals, and Cleveland Indians.

Pérez did well for a rookie after being called up by the Padres in 2002, striking out over a batter per inning, but he suffered from control issues at times.

[clarification needed] In August 2003, Pérez was sent by San Diego to Pittsburgh along with Jason Bay and Cory Stewart in exchange for Brian Giles.

His average of 10.97 strikeouts per nine innings was highest in the Majors (239 SO/196 IP); his 2.98 ERA was fifth in the National League (tied with Roger Clemens); and his 12–10 record could have been ever better with reasonable run support early in the season.

Pirates' bats provided two or fewer runs in Pérez' 16 starts before All-Star break, causing him to post a 5–4 record with five no decisions despite a 3.24 ERA.

The Pirates were forced to place him on the disabled list on June 29 after he broke his toe kicking a cart following a loss to St. Louis.

He missed two and a half months, returning in September to post a 4.58 ERA in 19.2 late season innings.

On June 29, he was sent to the Triple-A Indianapolis Indians, with Tom Gorzelanny being called up to replace him in the starting rotation.

[1] On July 31, 2006, Pérez and Roberto Hernández were traded to the New York Mets in exchange for Xavier Nady.

After two subpar starts, Pérez threw a complete-game shutout against the Atlanta Braves in the second game of a doubleheader on September 6.

However, Pérez finished the 2007 season 15–10 with a 3.56 ERA, striking out 174 in 177 innings pitched, while walking 79 (7th-most in the NL).

At the request of Pedro Martínez and pitching coach Dan Warthen, he changed his delivery to the plate.

[citation needed] On August 26, Pérez was diagnosed with patellar tendinitis in his right knee and underwent season-ending surgery.

Pérez refused a minor league assignment to work on his pitching, despite both his poor play and repeated attempts by the Mets' front office.

On January 19, 2012, the Seattle Mariners signed Pérez to a minor league deal with an invitation to spring training.

[19] In his first month back in the majors since 2010, observers took note of his improved fastball velocity and strikeout-to-walk ratio.

[21] On March 10, 2014, the Arizona Diamondbacks officially confirmed that Pérez had signed a two-year, $4.25 million contract.

[22] On August 8, 2015, the Arizona Diamondbacks traded Pérez to the Houston Astros for minor league pitcher Junior Garcia.

[24] On April 24, 2016, with the Nationals trailing the Minnesota Twins after 15 innings, and with two outs and Nationals shortstop Danny Espinosa on second base, Pérez hit a bunt that appeared to be rolling foul, but Minnesota catcher John Ryan Murphy picked it up and threw it away while attempting a putout at first, allowing Espinosa to score the tying run from second.

In the next inning, Washington right fielder Chris Heisey hit a leadoff home run to end the game, and Pérez was credited with the win.

[30] This is because under recent MLB rules changes, it was no longer necessary to actually pitch four balls in order to grant an intentional walk.

Melvin then had Chad Pinder (right) pinch-hit for Matt Joyce (left), so Francona countered by replacing Pérez with right-handed reliever Zach McAllister, thus making Pérez the first MLB pitcher to officially pitch in a game without actually throwing any pitches.

[32] With the 2020 Cleveland Indians, Pérez appeared in 21 games, compiling a 1–1 record with 2.00 ERA and 14 strikeouts in 18.0 innings pitched.