Cluzet has collaborated with many important European and American directors, including Claude Chabrol, Bertrand Tavernier, Claire Denis, Agnieszka Holland, Robert Altman and Olivier Assayas.

In 2007, he won a French César Award after starring as a doctor suspected of double homicide in the thriller Tell No One (original title Ne le dis à personne).

Cluzet next collaborated with a number of major name French directors, all of whom had a predilection towards dramatic works: reuniting with Kurys in 1983 for Coup de foudre, reuniting with Bertrand Tavernier (to co-star in jazz film Round Midnight in 1985), Tony Gatlif (Rue du départ, 1985), Claire Denis (Chocolat, 1987), Pierre Jolivet (Force majeure, 1988, and one new César nomination for best second male role), Bertrand Blier (Trop belle pour toi, 1989) and again Robert Enrico (La Révolution française).

He returned to French cinema and comedy in 1995 with Les Apprentis (César nomination for best actor) and Enfants de salaud with Tonie Marshall, following a new Claude Chabrol: Rien ne va plus in 1997.

Cluzet has often portrayed a role of the tormented writer: Fin août, début septembre with Olivier Assayas, L'Examen de minuit (1998), and Je suis un assassin (2004).