Members of the tumor necrosis factor receptor (TNFR) superfamily employ cytoplasmic adapter proteins called TNF-R associated factors (TRAF) to initiate and regulate signaling pathways. Although many of these receptors associate with TRAF3, it has been unclear how this TRAF functions in immune responses. New information appearing through the use of novel experimental models reveals that TRAF3 can mediate both activating and inhibitory signals, and can participate in regulation of multiple members of the TNFR superfamily. TRAF3 is also important for signaling via innate immune receptors, as well as an oncogenic mimic of a normal receptor that is implicated in promoting both malignancies and autoimmunity.