Cishek played in Major League Baseball (MLB) for the Florida / Miami Marlins, St. Louis Cardinals, Seattle Mariners, Tampa Bay Rays, Chicago Cubs, Chicago White Sox, Los Angeles Angels and Washington Nationals.

[4] In 2012, Heath Bell was demoted as the team's closer and Cishek assumed the role for about a week.

[5] Cishek flourished in 2013, his first full season as Miami's closer, converting 34 of his 36 save opportunities, while posting a 2.33 ERA and 1.08 WHIP.

[8] He debuted for the Cardinals on July 26 in a 3–2 loss to the Atlanta Braves, pitching one scoreless inning but being charged with an error on a pickoff attempt.

[10] On December 14, 2015, Cishek agreed to a two-year contract worth $10 million with the Seattle Mariners.

On July 28, 2017, the Mariners traded Cishek to the Tampa Bay Rays for Erasmo Ramírez.

[15] With the 2020 Chicago White Sox, Cishek appeared in 22 games, compiling a 0–0 record with 5.40 ERA and 21 strikeouts in 20.0 innings pitched.

[18] On February 9, 2021, Cishek signed a minor league contract with the Houston Astros organization that included an invitation to Spring Training.

[21] He appeared in 74 games with the Angels and compiled an 0-2 record with a 3.42 ERA and 64 strikeouts in 68.1 innings pitched.