Acute ischemic stroke is the third leading cause of death and the major cause of significant disability in adults in the USA and Europe. The number of patients who are actually treated for acute ischemic stroke is disappointingly low, despite availability of effective treatments. A major obstacle is the short window of time following stroke in which therapies are effective. Modern imaging is able to identify the ischemic penumbra, a key concept in stroke physiology. Evidence is accumulating that identification of a penumbra enhances patient management, resulting in significantly improved outcomes. Moreover, unexpectedly large proportions of patients have a substantial ischemic penumbra beyond the traditional time window and are suitable for therapy. The widespread availability of modern MRI and computed tomography systems presents new opportunities to use physiology to guide ischemic stroke therapy in individual patients. This article suggests an evidence-based alternative to contemporary acute ischemic stroke therapy.