The adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a central role in B cell activation pathways initiated by a wide variety of receptors, including members of the tumor necrosis factor receptor (TNFR) superfamily, Toll-like receptors (TLRs), cytokine receptors, and the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). TRAF6 has the most divergent receptor-binding TRAF-C domain among the TRAFs, and interacts with receptors in a manner distinct from that of other TRAFs. TRAF6 plays an important role in regulating a diverse range of processes in many cell types, including various important roles in the function of immune cells. This review focuses upon the molecular mechanisms of TRAF6 function in B lymphocyte activation, and the importance of TRAF6 in normal and pathologic B cell functions.