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Shatner began his screen acting career in Canadian films and television productions before moving into guest-starring roles in various American television shows. He appeared as James Kirk in all the episodes of Star Trek: The Original Series, 21 of the 22 episodes of Star Trek: The Animated Series, and the first seven Star Trek movies. He has written a series of books chronicling his experiences before, during and after his time in a Starfleet uniform. He has also co-written several novels set in the Star Trek universe and a series of science fiction novels, the TekWar sequence, that were adapted for television. Outside Star Trek, Shatner played the eponymous veteran police sergeant in T. J. Hooker (1982–1986), hosted the reality-based television series Rescue 911 (1989–1996), guest starred on the detective series Columbo, and acted in the comedy film Miss Congeniality (2000).

After his last appearance as Captain Kirk, Shatner's television career has embraced comedy, drama and reality shows. In seasons 4 and 5 of the NBC series 3rd Rock from the Sun, he played the alien "Big Giant Head", to which the main characters reported. From 2004 until 2008, he starred as attorney Denny Crane in the final season of the legal show The Practice and in its spinoff Boston Legal, a role that earned him two Emmy Awards, one for his contribution to each series. In 2016, 2017 and 2018, he starred in both seasons of NBC's Better Late Than Never, a comical travel series in which a band of elderly celebrities toured East Asia and Europe.

Aside from acting, Shatner has had a career as a recording artist, beginning in 1968 with his album The Transformed Man. His cover versions of songs are dramatic recitations of their lyrics rather than musical performances: the most notable are his versions of the Beatles' "Lucy in the Sky with Diamonds", Bob Dylan's "Mr. Tambourine Man", and Elton John's "Rocket Man". His most successful album was his third, Seeking Major Tom (2011), which includes covers of Pink Floyd's "Learning to Fly", David Bowie's "Space Oddity" and Queen's "Bohemian Rhapsody".

In 2021, Shatner flew into space aboard Blue Origin NS-18, a Blue Origin sub-orbital capsule. At age 90, he became the oldest person to fly in space and one of the first 600 to do so. Minutes after the flight, he described experiencing the overview effect.