The ubiquitination of proteins by E3 ligases has become an important regulatory mechanism for a variety of immune functions, including the maintenance of self tolerance and suppression of autoreactive T cell development. This review highlights recent advances in our knowledge of the functions in this context of known and potential E3 ligases, including autoimmune regulator (AIRE), TNF receptor-associated factor 6 (TRAF6), Casitas B cell lymphoma b (Cbl-b), gene related to anergy in lymphocytes (GRAIL), Itch, and Roquin. We discuss how disruptions to these molecules may contribute to the loss of T cell homeostasis and the pathogenesis of autoimmunity. We also report on the implications of the potential coordinated actions of these molecules for T cell anergy and regulatory T cell (Treg) functions. The great diversity of E3 ligases and the growing list of cellular processes in which ubiquitination plays a role make for an exciting field of research. Findings emerging from these investigations may suggest ways to exploit the therapeutic potential of manipulating ubiquitination, particularly for autoimmune disorders.