One of the crucial unanswered questions in the field of T-cell regulation is the origin of CD4þ CD25þ regulatory T cells. Does the thymus produce regulatory T cells as a functionally mature separate lineage, or can some T cells acquire regulatory function in the periphery? While mice live for 2Á5 years, humans can live for eight decades and beyond. The constraints on the persistence of human CD4þ CD25þ regulatory T cells will therefore be more extreme as a result of thymic involution early in the human lifespan. A central question is whether the full complement of CD4þ CD25þ regulatory T cells are generated early in life and if so, how do they manage to persist? A consistent observation in both mice and humans is that CD4þ CD25þ T cells in adults have the phenotypic characteristics of a highly differentiated T-cell population. This review seeks to reconcile the observations that CD4þ CD25þ T cells are anergic but highly differentiated. We suggest that it is possible that a subpopulation of CD4þ CD25þ regulatory T cells may arise in the periphery as a consequence of anergy induction in antigen-specific CD4þ T cells that are approaching end-stage differentiation.