He played in Major League Baseball (MLB) for the Tampa Bay Rays from 2006 through 2012, the Kansas City Royals in 2013 and 2014, the San Diego Padres in 2015 and 2016, and the Chicago White Sox from 2016 to 2018.

He declined a full scholarship to play baseball at Louisiana State University in favor of signing with the Tampa Bay Devil Rays.

His fastball lost some velocity as a result, forcing him to change his pitching approach and develop a changeup as he worked his way up through the Devil Rays system.

On May 9, he pitched nine shutout, three-hit innings, only to receive a no-decision due to lack of run support in an eventual 10-inning loss.

Later, on May 30, he pitched a complete game in a 5–3 win vs the Detroit Tigers in which, after a three-run first inning, he retired 13 straight batters.

Based on less than two full years of major league work with Tampa Bay, the Rays signed him to a four-year, $11.25 million contract after the 2008 season.

[10] After an injury to Tampa Bay's ace, Scott Kazmir, Shields made the 2008 Opening Day start for the Rays against Baltimore, earning the win by giving up two runs in seven innings in the 6–2 victory.

On April 27, 2008, Shields threw a two-hit complete game shutout against the Boston Red Sox, throwing only 98 pitches, for the first Maddux of his career.

On May 9 (exactly one year after his gem against Detroit), Shields had a one-hit shutout against the Angels, posting a Game Score of 93.

Shields stated afterward that he was protecting his teammates, believing that he did the right thing following an incident the night before involving Crisp.

[22] Despite continued success on the mound in 2012, Shields did not receive much run support from the Rays and finished the season with a record of 15-10 and a 3.52 ERA.

During his final start of the season on October 2, he pitched a complete game against the Baltimore Orioles, setting a franchise record with 15 strikeouts.

On December 9, 2012, Shields was traded to the Kansas City Royals (along with Wade Davis) in exchange for Wil Myers, Jake Odorizzi, Mike Montgomery and Patrick Leonard.

[23] In his first year as a Royal, Shields posted a 13-9 record with a 3.15 ERA, also setting a personal best in games started.

On May 13, 2014, in a 5-1 victory over the Colorado Rockies, Shields struck out Troy Tulowitzki in the sixth inning to record his 1,500th career strikeout.

On February 11, 2015, the San Diego Padres signed Shields to a four-year contract, worth $75 million, with a fifth-year club option.

[34] The White Sox declined the 2019 option on Shields's contract on October 29, 2018, making him a free agent.

[4] The couple is involved with The Heart Gallery and Eckerd Youth Alternatives, two initiatives benefiting children in foster care, and in 2010 donated a suite at Tropicana Field called "Big Game James Clubhouse" for the use of foster children attending games through the two initiatives.