Cellular-FLICE inhibitory protein (c-FLIP) is a key anti-apoptotic regulator that inhibits cell death mediated by the death receptors Fas, DR4, DR5, and TNF-R1. Three splice variants of c-FLIP function at the DISC level by blocking the processing and activation of procaspase-8 and -10. Overexpression of c-FLIP has been identified in many different tumour types, and its downregulation in vitro has been shown to restore apoptosis mediated by CD95L and TRAIL. c-FLIP therefore represents a promising target for cancer therapy. This review focuses on the molecular mechanisms that control c-FLIP expression and current research into inhibitors of the protein. Increasing evidence supports the investigation of c-FLIP as a therapeutic target to restore an apoptotic response in cancer cells.