At the cellular level, the multifunctional cytokine tumor necrosis factor (TNF) modulates growth and activates genes through various intermediates, including protein kinases, protein phosphatases, reactive oxygen intermediates, phospholipases, proteases, sphingomyelinases, and transcription factors. Unlike many cytokine receptors, however, the cytoplasmic domain (CD) of the TNF receptors lacks an intrinsic protein kinase activity and yet on interaction with ligand it phosphorylates various proteins. Although the kinetics of most of these activities differ, their interactions are coordinated through the selective interplay between the CD of the receptors and the associated proteins. A unique pathway has been identified by the ability of the TNF receptors to associate with a novel family of proteins. Two distinct families of proteins have emerged, the TNF receptor‐associated factors (TRAFs) and the death domain homologues. The cloning of members of these gene families and the identification of the protein‐interaction motifs found within their gene products has initiated the molecular identity of factors (TRADD, FADD/MORT, RIP, FLICE/ MACH, and TRAFs) associated with both of the p60 and p80 forms of the TNF receptor and with other members of the TNF receptor superfamily. In this review, we summarize these and other TNF receptor‐associated proteins and their potential roles in regulating the activation of nuclear factor‐κB and apoptosis, two major responses activated by engagement of TNF receptors by the ligand. J. Leukoc. Biol. 61: 559–566; 1997.