The tumor necrosis factor (TNF) superfamily consists of a wide variety of cell-bound and secreted proteins that regulate numerous cellular processes. In particular, TNF-family proteins regulate the proliferation and death of tumor cells, as well as activated immune cells. This overview discusses the mammalian TNF receptor-associated factors (TRAFs), of which TRAF1, 2, 3, 5, and 6 have been shown to interact directly or indirectly with members of the TNF receptor superfamily. Structural features of TRAF proteins are described along with a discussion of TRAF-interacting proteins and the signaling pathways activated by the TRAF proteins. Finally, we examine the phenotypes observed in TRAF-knockout mice.