Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (PubMed:18455983, PubMed:30361383, PubMed:30381458, PubMed:31511692, PubMed:31748744, PubMed:33397971). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:9654089, PubMed:9837723, PubMed:24813849, PubMed:24813850). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (By similarity). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A (PubMed:29440439). The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (By similarity). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (By similarity). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (By similarity). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-325', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31511692). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (PubMed:30361383, PubMed:30381458). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (PubMed:30361383, PubMed:30381458). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (PubMed:32971525). May participate in the Granzyme B (GZMB) cell death pathways (By similarity). Cleaves PARP1 (By similarity). Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala). CASP8 activity is restricted by RIPK1. (Microbial infection) Inhibited by baculovirus p35 protein P35. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (By similarity). Interacts with CFLAR and PEA15 (By similarity). Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (By similarity). Interacts with TNFAIP8L2 (PubMed:18455983). Interacts with CASP8AP2 (PubMed:17245429). Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15383280). Interacts with UBR2 (By similarity). Interacts with RIPK1 (PubMed:31519887). Interacts with FADD (PubMed:29440439). Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (By similarity). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (PubMed:34471287). Expressed in a wide variety of tissues. Highest expression in spleen, thymus, lung, liver and kidney. Lower expression in heart, brain, testis and skeletal muscle. In the embryo, highest expression occurs at day 7. Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease (PubMed:31511692). GZMB and CASP10 can be involved in these processing events (By similarity). (Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein. Phosphorylation on Ser-389 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes (By similarity). Embryonic lethality at lethality at 10.5 dpc (PubMed:9729047). Embryos display impaired heart muscle development and congested accumulation of erythrocytes (PubMed:9729047). Perinatal lethality observed in Ripk1 knockout mice is rescued in knockout mice lacking both Ripk1 and Casp8; mice however die the first days of postnatal life (PubMed:24813849). Only mice lacking Ripk1, Ripk3 and Casp8 survive past weaning and rescue lethality caused by the absence of Ripk1 (PubMed:24813849, PubMed:24813850). Belongs to the peptidase C14A family.