The controversial field of interventional stroke neurology has attracted considerable interest within the stroke community, but no endovascular interventional therapies have proved to be superior to intravenous (IV) recombinant tissue plasminogen activator (rtPA), the standard of care for patients with acute ischemic stroke. In this article, we review the evidence and background of IV thrombolysis for stroke, the clinical application of IV rtPA in practice, and the management of potential complications after thrombolysis. We conducted this review using a search of PubMed for articles published from January 1, 1995, to October 31, 2013, with the following terms: ischemic stroke, tissue plasminogen activator, TPA, alteplase, thrombolysis, and intracranial hemorrhage. Articles were also identified through searches of reference lists and the authors’ files. In nearly 2 decades since the publication of the transformative National Institute of Neurological Disorders and Stroke trials, the efficacy and safety of IV rtPA has been consistently verified in international real-world clinical practice. Time from stroke symptom onset to thrombolysis is crucial and probably the most important determinant of success of IV therapy. Thus, optimal care of patients with acute stroke should include community education and standardized protocols to guide immediate patient assessment and triage to medical centers with capability for efficient neurologic assessment, brain imaging, drug administration, and specialized postthrombolysis care.