The statins are a group of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase that are used extensively in medical practice because of their ability to reduce cardiovascular mortality and stroke. Although this protective activity was initially ascribed to the inhibition of cholesterol biosynthesis in the liver, clinical trials and basic research studies indicate that, beyond their cholesterol-lowering activity, statins might affect the function of different cell types in extrahepatic tissues. Here we will review the different mechanisms by which the statins exert their immunomodulatory and anti-inflammatory functions. We propose that statin pleiotropism is a key to the explanation of these activities, as it enables statins to act cooperatively in various steps of the inflammatory reaction, including terminal differentiation of immune cells, endothelial cell function, and regulation of the molecules that steer these cells to the sites at which they exert their immunomodulatory activity.