Hydroxymethylglutaryl-coenzyme A inhibitors (HMG-CoA inhibitors, or statins) were initially identified as fungal extracts in 1976 (1). They were subsequently developed as cholesterol-lowering drugs, and have been shown in numerous clinical trials to reduce both cardiovascular morbidity and mortality (2–6). However, studies also revealed that statins yield a larger mortality benefit than can be readily explained by their cholesterol-lowering effects alone, since their benefits occur too quickly to be explained by effects on atherosclerotic plaque (7), and are greater than lipid-lowering alone would predict (8). Additionally, statins appear to have beneficial effects on human diseases, such as multiple sclerosis (MS)(9) and osteoporosis (10), that have no direct association with cholesterol levels. These findings, together with growing awareness that atherosclerosis is itself an inflammatory disease, led to the suggestion that, in addition to lowering cholesterol, statins modify atherosclerosis via antiinflammatory mechanisms. A broader hypothesis followed naturally: that statins might have general antiinflammatory and/or immunomodulatory effects. Research over the last 10 years has elucidated a number of mechanisms by which statins may exert antiinflammatory effects (7, 11). In this article, we review the mechanisms of the action of statins, and the specific signaling pathways they modulate. We summarize the known potential antiinflammatory and immunomodulatory effects of statins at the cellular level. Finally, we review the data on the possible efficacy of statins in autoimmune/inflammatory diseases in both animal models and human trials.