Due to the random generation of T cell antigen receptors, a large fraction of developing T cells have the potential to recognize self-determinants. To prevent this self-reactive T cell repertoire from mediating autoimmunity, the immune system utilizes several mechanisms to induce tolerance to self. The majority of self-reactive T cells undergo negative selection (i.e., apoptosis) during development if their antigen receptors have high affinity for MHC-self-peptide complexes present in the thymus. Nonetheless, some T cells recognize self-epitopes that are not present in the thymus, and will thus reach maturation and migrate to peripheral lymphoid organs were they can be subject to a number of peripheral tolerance mechanisms such as deletion, inactivation (i.e., anergy) or suppression. While peripheral tolerization of naive (i.e., antigen-inexperienced) T cells has been studied extensively, there are potential situations in which self-reactive T cells might first encounter immunogenic forms of antigen (deriving from pathogens or vaccines) and thus be programmed to develop effector and memory functions. This article will review recent studies that have explored the potential of effector and memory T cells to undergo peripheral tolerization, as well as potential implications of these findings for autoimmunity and tumor-immunity.