Peroxisome proliferator-activated receptors (PPARs) are a group of lipid-activated nuclear receptors which regulate genes involved in lipid and glucose metabolism. PPAR-α is highly expressed in liver, heart, muscle and kidney, as well as in cells of the arterial wall, while PPAR-γ is expressed at high levels in white adipose tissue, where it activates adipocyte differentiation1. The discovery that PPAR-γ is also highly expressed in foam cells (activated macrophages that play a major role in the pathogenesis of atherosclerosis) raised many questions about the roles of PPAR-γ and its ligands in cardiovascular disease2, 3. Three papers in this issue by Moore et al. 4, Chawla et al. 5 and Chinetti et al. 6 provide support for an anti-atherogenic role of PPAR-γ. The papers also provide new models to improve our understanding of the biological mechanisms of PPAR-s. Not surprisingly, interest in PPAR-γ research has recently increased. High affinity PPAR-γ ligands known as thiazolidinediones (TZDs) have been discovered to be an exciting new class of anti-diabetic drugs7. The explosion of new information has led to controversy about the identity of PPAR-‘natural’ligands, the tissues they target and the role of PPAR-γ in the development of colon carcinoma7, 8. There is even controversy over how to pronounce PPAR—some say “pee-pargamma” whereas others, including this author, prefer to pronounce each letter. A debate of tremendous clinical importance also concerns the role of PPAR-γ in cardiovascular disease. Previous work using a pre-macrophage cell line demonstrated that activation of PPAR-γ signaling enhanced macrophage differentiation, inducing expression of CD36, one of the cell’s ‘scavenger’receptors for the atherogenic low-density lipoprotein (LDL)(Fig. 1). According to the model, increased CD36 expression leads to an intracellular accumulation of cholesterol and production of natural PPAR-γ ligands. This leads to further activation of PPAR-γ, creating a vicious cycle of ever-increasing lipid accumulation and conversion of macrophages into atherogenic foam cells3, 9. However, PPAR-γ ligands have also been shown to reduce inflammatory cytokine production by macrophages, an effect which should be anti-atherogenic2, 10. Indeed, atherosclerosis is reduced, not increased, in rodents as well as patients treated with PPAR-γ ligands11. So, what is the role of PPAR-γ in atherosclerosis? Chinetti et al. 6 show that neither PPAR-α nor PPAR-γ activation induces foam-cell formation from human monocyte-derived macrophages. Moreover, Chawla et al. 5 and Moore et al. 4 created PPAR-γ− null embryonic stem cells to demonstrate that the nuclear receptor is not required for development of the macrophage lineage in vivo or in vitro. Why, then, has it been observed that PPAR-γ activation induces expression of CD36, leading to the vicious cycle of lipid accumulation in foam cells and increased PPAR-γ activity? The answer seems to be that this cycle is broken by opposing effects of PPAR-γ ligands (Fig. 1). Moore et al. 4 report that PPAR-γ ligands have an opposite effect on a second low-density lipoprotein scavenger receptor, SR-A, causing its downregulation in mouse macrophages. Additionally, Chinetti et al. 6 found that expression of ABCA1, a protein involved in cholesterol export, is activated by the LXR nuclear receptor, which is induced by PPAR-γ ligands. Thus, PPAR-γ ligands have multiple effects on influx and efflux of cholesterol and oxidized lipids, countering their potentially atherosclerotic effect of CD36 induction. PPAR-γ ligands also have inhibitory effects on macrophage cytokine production. These anti-inflammatory effects are consis-