3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) are drugs active in the blockade of cholesterol synthesis and thus lowering cholesterol serum levels. Since their discovery, experimental evidence showed that statins strongly reduced atherogenesis and the risk of acute ischemic complications, such as acute myocardial infarction and stroke. More recently, direct anti-atherosclerotic effects of statins (independently of lipid profile improvement) have been also shown, suggesting new potential applications for these drugs in both primary and secondary prevention of acute cardiovascular events. Despite some controversies exist, the use of statins has been shown to improve both incidence and survival in acute ischemic stroke. The molecular mechanisms underlying statin-mediated clinical benefits were recently identified in the reduction of carotid plaque vulnerability and the increase of neuroprotection. In the present review, we will update evidence on the promising results with statins to improve ischemic stroke outcomes.