In 2006 Caltagirone starred in The Path to 9/11, the controversial two part miniseries which aired in the United States on ABC. The film starring Harvey Keitel and Donnie Wahlberg dramatizes the events leading up to the September 11, 2001 attacks. Caltagirone was cast as one of the CIA operatives that were allegedly sent to kill Osama Bin Laden. In 2009, he played ex-SAS Captain Gideon Stone in The Fixer. He portrayed aristocrat Girolamo de Treviso in The Tudors in 2010. He starred at The Hampstead Theatre in .45 playing alongside fellow Tudors alumni Natalie Dormer in 2011. In 2016, he appeared in the TV series Medici: Masters of Florence.