The management of acute ischemic stroke has not made significant strides since the introduction of recombinant tissue plasminogen activator (r-TPA) two decades ago. The use of other therapies, such as heparin, aspirin, dipyridamole, and/or clopidogrel, have only moderately aided in the treatment of this ischemic disease. Therefore, major medical innovative approaches are critically needed. Because of the side effects associated with r-TPA (specifically bleeding) and its limited 3-h therapeutic window, new studies using current developments encountered in the molecular biology of ischemia are being incorporated into the potential therapy of ischemic stroke. A review of the major advances in the field, including glutamate receptor blockade, magnesium infusion, inflammation blockade, apoptosis inhibition, and other therapies, is introduced with special emphasis on the molecular findings recognized as targets for a better and more effective treatment. As new therapies are being considered, the time of administration is becoming a central point of study for the application of novel therapeutic initiatives.