Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a member of the TNF family and a powerful inducer of apoptosis in a wide range of human cancer cell lines via proapoptotic death receptor 4 (DR4; TRAIL-R1) and death receptor 5 (DR5; TRAIL-R2). The induction of apoptosis is accomplished via FADD/DISC/caspase-8 signaling in several cell types including neurons and oligodendroglia. This pathway is important in the pathogenesis of adult stroke, trauma, infection and multiple sclerosis (MS), but there is limited information available with respect to the involvement of TRAIL and its receptors in the demise of immature neurons, such as in neonatal Hypoxia-ischemia (HI). In humans, four membrane bound and one soluble receptor for TRAIL have been identified. On contrast with DR4 and DR5, DcR1 (TRAIL-R3), DcR2 (TRAIL-R4) and the soluble osteoprotegerin (OPG) lack functional death domains and are considered to function as decoy receptors.