Signal transduction pathways which are initiated by members of the TNF superfamily utilize receptors which are devoid of intrinsic catalytic activity. Isolation and characterization of death domain (TNF-RI, Fas, TRADD, FADD/MORT-1, RIP) and TRAF domain-containing proteins (TRAF-1, TRAF-2, TRAF-3) have partially bridged a large molecular gap within one of several signaling pathways which originate at the plasma membrane and terminate in the nucleus. The ability of these two protein families to selectively dimerize and bind to related receptors allows them to govern diverse cellular responses which culminate in cellular proliferation, differentiation, effector functions, and apoptosis.