Self-reactive T cells that escape negative selection in the thymus must be inactivated in the periphery. Anergy constitutes one means of imposing peripheral tolerance. Anergic T cells are functionally inactivated and unable to initiate a productive response even when antigen is encountered in the presence of full co-stimulation. Recent studies have provided new insights into the mechanisms responsible for the induction and maintenance of T-cell anergy. These studies have helped clarify the nature of the signals that induce tolerance, the cells able to deliver them and the molecular processes that underlie the unresponsive state.