Selective suppression of effector CD4+ T cell functions is necessary to prevent immune cell–mediated damage to healthy tissues. This appears especially true during pregnancy or in individuals predisposed to autoimmunity. Foxp3+ regulatory T (T reg) cells and induction of anergy, an acquired state of T cell functional unresponsiveness in Foxp3− cells, have both been implicated as mechanisms to suppress dangerous immune responses to tissue-restricted self-Ags. Anergic CD4+ T cells and T reg cells share a number of phenotypic and mechanistic traits—including the expression of CD73 and folate receptor 4, and the epigenetic modification of T reg cell signature genes—and an interesting relationship between these two subsets has recently emerged. In this review, we will compare and contrast these two subsets, as well as explore the role of anergy in the generation of peripheral T reg cells.