He played in Major League Baseball (MLB) for the San Francisco Giants, Los Angeles Dodgers, Tampa Bay Rays, Miami Marlins, Minnesota Twins, Oakland Athletics, Seattle Mariners, and Toronto Blue Jays.

A free agent after the season, he signed with the Marlins and served as Miami's closer until getting traded to the Twins halfway through the year.

[3] Work responsibilities kept Frank, a semipro player, from being able to play Minor League Baseball, and he wanted to make sure his son got the opportunity.

[3] Romo played shortstop and third base on the baseball team at Brawley Union High School, graduating in 2001.

He made 41 relief appearances for the San Jose Giants of the Single-A advanced California League in 2007, compiling a 6–2 record, a 1.36 ERA, 106 strikeouts, and nine saves in 66+1⁄3 innings of work.

[16] He made his big league debut on June 26, 2008, in a 4–1 loss to the Cleveland Indians, striking out two in an inning pitched.

In mid-June, Giants' manager Bruce Bochy removed the struggling Guillermo Mota from the setup role and replaced him with Romo, who held it for the rest of the regular season.

[24][25] Romo gained notoriety for being one of the team's relief pitchers with a prominent beard, along with LHP Jeremy Affeldt and closer Brian Wilson.

[8] In Game 2 of the National League Division Series (NLDS) against the Atlanta Braves, Romo gave up two hits without recording an out; both runners scored as the Giants went on to blow a three-run lead and lose 5–4 in 11 innings.

[29] In Game 4 of the NL Championship Series (NLCS) against the Philadelphia Phillies, Romo gave up an RBI double to Jayson Werth and was charged with a blown save, but the Giants won 6–5.

[31][32] Romo made one appearance in the World Series against the Texas Rangers, throwing 2⁄3 of a scoreless eighth inning in the Giants' 11–7 victory.

[37] Bochy announced on August 7 that the Giants would use a "bullpen by committee" strategy, with Romo, Javier López, and Jeremy Affeldt pitching the final two innings of close games, depending on which hitters they would be facing.

[40] Romo appeared in 69 games of the 2012 season, earning 14 saves with a 1.79 ERA, which was fourth among NL relievers and trailed only Craig Kimbrel (1.01), Aroldis Chapman (1.51) and Eric O'Flaherty (1.73).

[8] On July 14, he was added to the NL All Star Game roster after Jeff Locke and Jordan Zimmermann made starts on Sunday and became ineligible to pitch.

[52] The Giants reached the playoffs for the fourth time in Romo's tenure with them, winning the NL Wild Card Game against the New York Mets.

[63] With the Giants leading Game 3 of the NLDS against the Chicago Cubs by a score of 5–3, Romo was called on to get the save in the ninth inning.

[68] On July 22, 2017, the Dodgers traded Romo to the Tampa Bay Rays for cash considerations or a player to be named later (PTBNL).

[8] In 55 games combined between Los Angeles and Tampa Bay, he had a 3–1 record, no saves, a 3.56 ERA, and 59 strikeouts in 55+2⁄3 innings pitched.

[70] That season, Rays manager Kevin Cash decided to experiment with using an opener, a pitcher designated to pitch the first one to three innings at the beginning of a ballgame.

Instead, having a relief pitcher start the game will allow the regular starter (or "bulk guy") to enter later and reach later innings without having to face as many hitters.

[8] That day, the Marlins traded Romo, Chris Vallimont, and a PTBNL to the Minnesota Twins in exchange for Lewin Díaz.

[8] He appeared in a total of 65 games between Miami and Minnesota, compiling a 2–1 record, a 3.43 ERA, 20 saves in 23 chances, and 60 strikeouts in 60+1⁄3 innings.

[87][88] In Game 2 of the ALDS, he got the first two outs of the eighth inning without surrendering a run; however, the Twins lost to the New York Yankees by a score of 8–2.

[52] On December 16, 2019, Romo elected to return to the Twins for the 2020 season, signing a 1-year, $5 million deal with a team option for 2021.

[92][93][94] In a 3–1 win over the Cleveland Indians on September 11, Romo retired Francisco Lindor on a fly ball to end the eighth inning.

Romo then walked Jose Altuve to force in a run before getting replaced on the mound by Caleb Thielbar, who gave up a two-run single to Michael Brantley.

[99] On October 28, the Twins declined to exercise their $5 million option on Romo's contract for the 2021 season, giving him a $250,000 buyout and making him a free agent.

On July 20, Romo cleared waivers and was sent outright to the Triple-A Buffalo Bisons, but rejected the assignment and elected free agency that same day.

Following the 2016, 2017, and 2018 MLB seasons, Romo played for the Charros de Jalisco of the Mexican Pacific League.

[14] With a low-three quarters delivery, Romo features four pitches: an unusual "No Dot" slider, a fastball, a sinkerball, and a changeup.