Cells that escape negative selection in the thymus must be inactivated or eliminated in the periphery through a series of mechanisms that include the induction of anergy, dominant suppression by regulatory T cells, and peripheral deletion of self‐reactive T cells. Calcium signaling plays a central role in the induction of anergy in T cells, which become functionally inactivated and incapable of proliferating and expressing cytokines following antigen re‐encounter. Suboptimal stimulation of T cells results in the activation of a calcium/calcineurin/nuclear factor of activated T cells‐dependent cell‐intrinsic program of self‐inactivation. The proteins encoded by those genes are required to impose a state of functional unresponsiveness through different mechanisms that include downregulation of T‐cell receptor signaling and inhibition of cytokine transcription.