To ensure that efficient immune responses against dangerous antigens are raised while tolerance to self molecules is preserved, the immune system tightly regulates activation and survival of its cellular compartments through mechanisms only partially characterized. In this context, recent evidence indicates a role in immunity of the nuclear receptor PPAR-gamma, which is upregulated in activated lymphocytes and in dendritic cells. Preliminary in vitro studies indicate that PPAR-gamma activation profoundly alters the immune properties of these cells, usually leading to the inhibition of immune responses. Naturally occurring PPAR-gamma ligands include the cyclopentenone prostaglandins of the J series, which are present in bone marrow, thymus, and secondary lymphatic tissues. The levels of these metabolites are increased in inflamed tissues, where they exert strong anti-inflammatory effects leading to resolution of inflammation and wound healing. Cyclopentenone prostaglandins activate both PPAR-gamma-dependent and PPAR-gamma-independent pathways, possess intrinsic proapoptotic potential and are direct inhibitors of NF-kappaB signaling. The relevance of these effects in vivo still awaits proper evaluation in humans. Some of the newly described regulatory pathways might eventually be exploited in the treatment of immune diseases by means of PPAR-gamma ligands, such as thiazolidinediones or prostaglandins.