The presentation of self-peptide-MHC complexes in the periphery to potentially autoreactive T cells that have escaped negative selection in the thymus poses an important problem to the immune system. In this review, I discuss data that reveal barriers preventing peripheral T cell recognition of self-peptide-MHC complexes, as well as the physiological mechanisms that ensure the elimination or functional inactivation (anergy) of T cells that do come to recognize self-peptide-MHC and threaten the health of the individual.