Stroke is the third leading cause of death after myocardial infarction and cancer and the leading cause of permanent disability and of disability-adjusted loss of independent life-years in Western countries. Thrombolysis is the treatment of choice for acute stroke within 3 hours after symptom onset. Treatment beyond the 3-hour time window has not been shown to be effective in any single trial; however, meta-analyses suggest a somewhat less but still significant effect within 3 to 6 hours after stroke. It seems reasonable to apply improved selection criteria that would allow one to differentiate patients with a relevant indication for thrombolytic therapy from those who do not have one. We present an overview of a diagnostic approach to acute stroke management that allows the clinician to individualize patient management based on pathophysiologic reasoning and not rigid time windows established by randomized controlled trials. Therefore, this review concentrates on giving the reader an integrated knowledge of the current status of thrombolytic therapy in stroke and then develops a treatment algorithm based on pathophysiologic information rendered by a multiparametric stroke magnetic resonance imaging protocol.