Until recently ubiquitination of a protein was thought to simply serve the mundane task of targeting a protein for proteasomal degradation. Accumulating evidence over the past decade has demonstrated the importance of ubiquitination in non-degradative functions including regulating cellular signaling, that highlight its role in human disease and thus potential development of novel therapeutics. Much has been written about ubiquitination in the immune system, in this review we will outline our current knowledge of ubiquitination with respect to T cell tolerance. Specifically, we will provide on overview of E3 ubiquitin ligases and their role in various states of CD4+ T cell tolerance: central and peripheral.