CTLA-4 is a potent co-inhibitory molecule that is critical for peripheral T cell tolerance. A report in this issue reveals the autoantigen-specific nature of CTLA-4-deficient CD4+ T cells within target tissue. In vivo studies demonstrate that CTLA-4 expression by self-reactive effector cells is sufficient to limit their infiltration into target tissue and that regulatory T cells expressing CTLA-4 can control autoantigen-specific effector T cells. Thus, these findings provide evidence that CTLA-4 exerts its critical immunoregulatory functions by controlling conventional T cells as well as regulatory T cells.