Initially described as an adaptor molecule for death receptor (DR)-mediated apoptosis, Fas-associated death domain (FADD) was later implicated in nonapoptotic cellular processes. During the last decade, FADD has been shown to participate and regulate most of the signalosome complexes, including necrosome, FADDosome, innateosome, and inflammasome. Given the role of these signaling complexes, FADD has emerged as a new actor in innate immunity, inflammation, and cancer development. Concomitant to these new roles, a surprising number of mechanisms deemed to regulate FADD functions have been identified, including post-translational modifications of FADD protein and FADD secretion. This review focuses on recent knowledge of the biological roles of FADD, a pleiotropic molecule having multiple partners, and its impact in cancer, innate immunity, and inflammation. FADD is part of most signalosome complexes including the necroptosome, FADDosome, innateosome and inflammasome. Human FADD gene can be a potential driver in cancer through its amplification, which has been associated with both metastasis and poor overall survival for certain malignancies. FADD has been implicated in immune defenses against bacterial and viral infections, and a human FADD missense mutation has led to severe and potentially lethal, infectious diseases. FADD activity can be modulated by several post-translational modifications (phosphorylation, SUMOylation, ubiquitination, cleavage, and arginine GlcNAcylation) as well as via its cellular localization (nuclear/cytoplasmic/extracellular). FADD might play a critical role in cancer, innate immunity, and inflammation. The role of FADD in tumoral and inflammatory responses may be dual, with FADD exerting either anti- or protumoral/inflammatory effects, depending the cell type and model.