Acute ischemic stroke (AIS) is a time sensitive medical emergency and a leading cause of morbidity and mortality worldwide. Intravenous (IV) recombinant tissue plasminogen activator (IV alteplase) is currently the only proven effective medication for the treatment of AIS with promising adjuvant medications currently under investigation. Recent advances in endovascular thrombectomy have broadened therapeutic options in specific patient populations, with modern treatment strategies utilizing advanced imaging modalities to extend the window for treatment. In all cases, rapid treatment remains a priority. The future of IV alteplase and the changing standard for treatment of AIS remain unwritten with the increasing evidence for imaging selection for both endovascular thrombectomy and IV alteplase, while novel adjuncts are under investigation. In this article, we review the history of IV alteplase investigations for stroke, evidence for thrombectomy as an adjunct to IV alteplase, and the potential of novel adjuvant therapeutics currently under investigation.