Intensive efforts are presently directed toward developing pharmacologic therapy to protect the ischemic brain. Preclinical data from animal models indicate that insulin, already available for human use, may reduce damage in both global and focal ischemia. Two kinds of mechanisms may be involved: one in which insulin interacts directly with brain tissue and one in which insulin acts indirectly by reducing peripheral blood glucose levels. Animal data indicate that part of the former, direct mechanism is mediated by insulin-like growth factor-1 receptors. The direct effect appears to predominate in global ischemia. In focal ischemia, unlike global ischemia, the effect of insulin is predominantly via peripheral hypoglycemia, because neuroprotection is largely annulled by co-administration of glucose. The two clinical counterparts of global and focal ischemic models are, respectively, cardiac arrest encephalopathy and focal ischemic stroke. Insulin use in both of these clinical situations could be evaluated in clinical trials that attempt to reduce ischemic brain damage, because insulin has a long and safe history of human use in diabetes treatment.