The vertebrate immune system has evolved to deal with invasive pathogens, but this adaptation comes at the expense of immunopathology. Among a number of mechanisms that coevolved to control adaptive immunity is anergy, the functional inactivation of T lymphocytes that respond to Ag in the absence of inflammation. In this review, I highlight a series of intracellular proteins in quiescent T cells that function to integrate signals from Ag, costimulatory, and growth factor receptors. These factors ensure that cells that fail to engage all three pathways are shunted into an alternative transcriptional program designed to dissuade them from participating in subsequent immune responses. Recent studies indicate that anergy is the combined result of factors that negatively regulate proximal TCR-coupled signal transduction, together with a program of active transcriptional silencing that is reinforced through epigenetic mechanisms.