Contributing to the “death signal”, CYLD deubiquitylates TRAF2 and RIPK1, allowing the formation of the ripoptosome.37–41 The mitochondrial protein Smac further promotes necroptosis by triggering proteasomal degradation of cIAP1/2 and XIAP.42 Consequently, Smac mimetics have been developed as therapeutic tools against cancer cells or HIV-infected cells.43–45 These agents and other anticancer drugs promote the formation of the ripoptosome through depletion of XIAP and cIAP1/2 independent of death receptor activation.11 The gene discussed is XIAP; the disease is cancer.