Statins, which are mainly used for treatment of hypercholesterolemia because of their lipid-lowering effects, may also display many immunomodulatory properties. Statins interfere in the mevalonate pathway through inhibition of HMG-CoA reductase activity and thereby affect isoprenylation of proteins and cholesterol biosynthesis. Besides lowering blood cholesterol levels, statins inhibit the production of pro-inflammatory cytokines and reduce membrane expression of several immunoregulatory molecules, including major histocompatibility complex class II (MHC-II) molecules. In this review we discuss the putative immunomodulatory role of statins and the mechanism by which simvastatin reduces the membrane expression of MHC-II molecules on several cell types, emphasizing on the disruption of cholesterol-containing microdomains, or lipid rafts, which transport and concentrate MHC-II molecules to the cell surface. Because glycosylphosphatidylinositol (GPI)-linked proteins are in general characteristic components of biochemically defined lipid rafts, and rely for transport and function at the cell surface on the integrity of these cholesterol-containing vesicles, we argue that statins, by disrupting these vesicles, also affect the expression of other immunoregulatory molecules. In addition, we also argue that statins inhibit the activation and intracellular transport of various proteins by interfering in protein isoprenylation. The interference in these processes results in reduced expression and function of membrane-bound molecules, which play important roles in the initiation and effector function of the immune response. Finally, we discuss the potential role of statins in the treatment of neuroinflammatory diseases.