Immunosuppressive and anti-inflammatory agents are able to generate tolerogenic DCs, leading, in some cases, to induction or enhancement of regulatory T cells with suppressive activity. This novel mechanism of action, shared by several immunosuppressive and anti-inflammatory agents, is becoming firmly established and contributes to explain their functional properties. The possibility to manipulate DCs in vivo using more or less conventional low molecular weight drugs, enabling them to exert tolerogenic activities, could be exploited to better control a variety of chronic inflammatory conditions, from autoimmune diseases to allograft rejection.