Antigen-specific unresponsiveness (or tolerance) has always been an important area of research. Interest in the fate of apoptotic cells and their ability to tolerize has revived interest in some of the older models involving hapten-modified self. Recently, we have examined the mechanisms by which intravenous injection of trinitrophenol-coupled spleen cells leads to systemic tolerance. These studies have revealed an important role for Fas/Fas ligand interactions, caspases, CD40/CD40L, and regulatory CD4+ and CD8+ T cells. Extension of these studies to peripheral deletion of T-cell antigen receptor transgenic T cells has shown that deletion and active regulation of immune responses may be important mechanisms for the control of potentially damaging autoimmune responses.