Beside aspirin administration and stroke unit care, thrombolysis is the only approved and effective therapy in acute ischemic stroke. Thrombolysis is essentially limited by the short therapeutic window and its potential side effects. Although there is a robust body of evidence on the neuroprotective characteristics of hypothermia in animal models of focal ischemia, the clinical data on hypothermia in stroke are inconclusive in terms of effectiveness. Previous trials suggest that hypothermia is safe and feasible in stroke, and may decrease intracranial pressure (ICP) in patients suffering from space-occupying infarcts. However, neuroprotection by hypothermia has never been shown previously in stroke patients. This lack of efficacy might be explained by the fact that hypothermia is not appropriately used in patients and animal data are not correctly interpreted. This review summarizes the major conclusions of animal studies and presents results of clinical stroke trials to date. Methods of delivery and maintenance of hypothermia are discussed, as well as a variety of open questions in the relevant animal and clinical research.