The 2010 series is the second television adaptation of the Human Target comic book created by Len Wein and Carmine Infantino, following an earlier 1992 ABC series.

Jackie Earle Haley's character Guerrero was originally intended to appear only once in the pilot episode, with a different helper character planned for each subsequent episode, but producers liked Haley's performance so much they made him a series regular.

After Fox renewed the show for a second season, Warner Bros. asked incoming showrunner Matt Miller to review the first season and suggest changes, leading him to replace original developer Jonathan E. Steinberg as showrunner.

The series was filmed in Vancouver, British Columbia.

Composer Bear McCreary wrote about 30 minutes of full orchestral music per week for 11 consecutive weeks during season one, performed by an average of 60 musicians.

The score for the first-season finale 'Christopher Chance' was performed by a total of 94 musicians, making it the largest live orchestra ever assembled for a television series at the time.

Bear McCreary was not brought back for season two because the production could no longer afford a weekly 40-person orchestra, so Chuck composer Tim Jones took over scoring duties.

Several critics and viewers reacted negatively to the season two change in the opening title theme music, with one reviewer stating the change 'just plain sucked.'