Activation of T lymphocytes relies on the simultaneous delivery of signals from the T cell receptor and co-receptors such as CD28. The absence of co-receptor signaling leads to a state of unresponsiveness called anergy, which prevents T cells from reacting against self antigens. The biochemical program that ensures the induction of anergy uses several mechanisms, including the synthesis of ubiquitin E3 ligases such as Cbl-b (Casitas B-lineage lymphoma). Because these E3 ligases function as gatekeepers to prevent the undesired activation of T cells, full and productive induction of the T cell response requires the restriction of these negative regulators by mechanisms that we are beginning to understand.