Neuroprotection remains one of the holy grails of acute ischemic stroke therapy. The ability to protect the ischemic brain from injury until reperfusion and then to protect the brain from reperfusion injury could theoretically improve freedom from disability among stroke survivors. This manuscript reviews the molecular and cellular pathophysiology of stroke and summarizes pharmacologic and other therapies that showed promise in pre-clinical testing as neuroprotection agents. However to date, no compelling efficacy data have been published regarding any pharmacologic or other therapies. Nonetheless the search for effective neuroprotection continues at stroke centers throughout the world. (C) 2017 Elsevier Inc. All rights reserved.