Abstract Programmed or apoptotic-like cell death plays an important role in cell demise following ischemic or traumatic brain injury. Caspases -1, -3, -8, and -11, the pro-death bcl-2 family member BID, and the Fas death receptor have been implicated. We recently showed that caspases-8 and -3 are activated, BID is cleaved in mouse brain after cerebral ischemia, neuronal BID is a substrate of caspase-8, and that Bid null mice are resistant to ischemia. These novel findings suggest that BID promotes caspase activation and contributes importantly to ischemic neuronal cell death. Consistent with its role in programmed cell death, caspase-3 null mice are resistant to mild ischemia, and in vitro neuronal death was inhibited in cultured caspase-3 −/− neurons subjected to OGD. Interestingly, we observed that caspase-3 substrates such as poly(ADP-ribose) polymerase (PARP) are still cleaved in the absence of caspase-3, albeit in reduced amounts. Upstream, the Fas death receptor is an important initiating mechanism of cell death after ischemia and TBI. Fas expression and Fas–Fas ligand interaction is markedly increased in injured brain early after experimental traumatic brain injury (TBI), and Fas activation is followed by robust assembly of Fas–Fas-associated protein with a death domain (FADD)–procaspase-8 death inducing signaling complex (DISC) assembly within hours. DISC assembly is temporally associated with cleavage of caspases-8 and -3 and neuronal cell death, and robust assembly of Fas DISC occurs in contused human brain after TBI. All of the components needed to assemble a DISC are intrinsic to neurons based on in vitro studies. Fas ligand overexpression induces DISC assembly in cultured neurons, and resultant cell death is attenuated by adding a broad spectrum caspase inhibitor. Together, these data suggest that death receptors play an important role in initiating caspase-mediated cell death after TBI, and that death receptors or their downstream DISC components may be attractive therapeutic targets to reduce cell death after CNS injury.