Stimulation of TNFR1 by TNF results in differential activation of proinflammatory and proapoptosis pathways. TNFR1 activation results in complex formation between RIPK1 and TNFR1-associated death domain (TRADD) protein and other accessory proteins. Ubiquitinylation of RIPK1 by cellular inhibitor of apoptosis proteins (cIAPs) or linear ubiquitin chain assembly complex (LUBAC) results in recruitment of the inhibitor of I-κB kinase (IKK) complex, leading to nuclear translocation and activation of NF-κB. NF-κB regulates transcriptional activation of genes important for cell survival, proinflammatory cytokines, and apoptosis-related proteins. Alternatively, a second deubiquitinylated complex of RIPK1 associates with Fas-associated death domain (FADD) protein and pro–caspase-8. The resulting caspase-8 activation leads to activation of the extrinsic apoptosis pathway, and activation of effector caspase-3 and -7, culminating in apoptosis. Under conditions of caspase-8 depletion or cIAP deficiency, stimulation of TNFR1 promotes the necroptosis pathway. Necrosome formation involves RIPK1/RIPK3 interaction and activation of MLKL. Alternative receptor/ligand interactions, such as stimulation of TLR3/TLR4 by dsRNA or LPS or sensing of viral DNA by DNA-dependent activator of IFN-regulatory factors (DAI), leads to the formation of a TRIF-RIPK3 complex or DAI-RIPK3 complex and RIPK1-independent necrosome formation. Phospho-MLKL (p-MLKL) oligomerizes and translocates into the plasma membrane, where it causes membrane rupture and release of DAMPs. TRAF, TNF receptor associated factor; TRAIL, TNF-related apoptosis-inducing ligand; TRIF, Toll/IL-1 receptor domain–containing adapter-inducing IFN-β.