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Gatiss co-created, co-wrote and acted in the BBC comedy series The League of Gentlemen (1999–2002). He co-created and portrayed Mycroft Holmes in the BBC series Sherlock (2010–2017) and Frank Renfield in the BBC / Netflix miniseries Dracula (2020). He also wrote several episodes of Doctor Who during Moffat's tenure as showrunner and two episodes during Russell T Davies' earlier tenure. His other TV roles include Tycho Nestoris in Game of Thrones (2014–2017), Stephen Gardiner in Wolf Hall (2015), and Peter Mandelson in Coalition (2015). He has acted in films such as Victor Frankenstein (2015), Denial (2016), Christopher Robin (2018), The Favourite (2018), The Father (2020), Operation Mincemeat (2021), and Mission: Impossible – Dead Reckoning Part One (2023).

On stage, Gatiss played Menenius in the revival of William Shakespeare's Coriolanus (2013), for which he earned a Laurence Olivier Award for Best Actor in a Supporting Role nomination. He took on the role of King George III in a revival of the Alan Bennett play The Madness of George III (2018). He portrayed Sir John Gielgud in the Jack Thorne play The Motive and the Cue (2023), for which he earned the Laurence Olivier Award for Best Actor. His other theatre roles include The Recruiting Officer (2012), The Vote (2015), and A Christmas Carol: A Ghost Story (2021).