TRAF6 is divergent from other members of the TRAF family. Therefore, TRAF6 was expected to play physiological roles distinct from those of other TRAFs. In this chapter, we focused on the physiological functions specific to TRAF6 but not other TRAFs in immune system, formation of skin appendices, and nervous system development by describing abnormal phenotypes observed in TRAF6-deficient mice. The role of TRAF6 in osteoclastogenesis and the molecular mechanisms ofTRAF6-mediated signal transduction are described in other chapters.