It is hypothesized that the anti-inflammatory actions of peroxisome proliferator-activated receptors (PPARs) may explain the protective effect of these receptors in diabetes, atherosclerosis, cancer and other inflammatory diseases. However, emerging evidence for pro-inflammatory activities of activated PPARs is concerning in light of new studies which associate PPAR modulators with an increased incidence of both cardiovascular events in humans and the sporadic formation of tumors in rodents. In an attempt to define the role of each PPAR subtype in inflammation, we made the unexpected observation that human PPARdelta is a positive regulator of inflammatory responses in both monocytes and macrophages. Notably, TNFalpha -stimulated cells administered PPARdelta agonists express and secrete elevated levels of inflammatory cytokines. Most surprising, however, was the finding that thiazolidinediones (TZDs) and other known PPARgamma ligands display different degrees of pro-inflammatory activities in a PPARgamma - and PPARalpha -independent manner via their ability to augment PPARdelta signaling. A series of mechanistic studies revealed that TZDs, at clinically relevant concentrations, bind and activate the transcriptional activity of PPARdelta. Collectively, these studies suggest that the observed pro-inflammatory and potentially deleterious effects of PPARgamma ligands may be mediated through an off-target effect on PPARdelta. These studies highlight the need for PPAR modulators with increased receptor subtype-specificity. Furthermore, they suggest that differences in systemic exposure and consequently in the activation of PPARgamma and PPARdelta may explain why TZDs can exhibit both inflammatory and anti-inflammatory activities in humans.