The first two members of the tumor necrosis factor receptor-associated factor (TRAF) family of proteins, TRAF1 and TRAF2, were identified as signal transducers of tumor necrosis factor (TNF) receptor type II (TNFRII) in 1994 [1]. Since then, four additional members of the TRAF family, TRAF3, TRAF4, TRAF5, and TRAF6, have been identified in human and mouse [2–10]. In addition, one TRAF of the nematode Caenorhabditis elegans [11] and two TRAFs of the Drosophila melanogaster [12] have been reported. As described below, identification of the TRAF family of proteins led to dramatic progress in the elucidation of the molecular mechanisms of signal transduction emanating from the TNFR superfamily and the Toll/interleukin-1 receptor (Toll/IL-1R) family. TRAF2, TRAF5, and TRAF6 serve as adapter proteins that link the cell surface receptors and downstream kinase cascades, which results in activation of transcription factors, nuclear factor κB (NFκB) and activator protein-1 (AP-1). Although neither TRAF1 nor TRAF3 activates any kinase tested so far in in vitro experiments, TRAF1 transgenic mice [13] and TRAF3-deficient mice [14] exhibit marked impairment in their immune systems. Thus, the TRAF-mediated signals apparently play important roles in regulating cell survival, proliferation, and stress responses. While TRAF family was growing, another group of adapter proteins, the death domain (DD) proteins, was shown to mediate the signals emanating from some of the TNFR superfamily and Toll/IL-1R family by binding to their cytoplasmic tails [15–17]. In such DD-protein-mediated signals, TRAFs either directly or indirectly bind to the DD protein to transduce the signals. Thus, the members of the TRAF family are key molecules in the signals regulating the immune and inflammatory systems.