Results These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. Conclusions These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke. (Stroke. 2019;50:e344 e418. Key Words: AHA Scientific Statements critical care disease management emergency medical services secondary prevention stroke therapeutics See related article, p 3331 New high-quality evidence has produced major changes in the evidence-based treatment of acute ischemic stroke (AIS) since the publication of the guidelines for the early management of patients with acute ischemic stroke in 2013.1 Much of this new evidence has been incorporated into American Heart Association (AHA) focused updates, guidelines, or scientific statements on specific topics relating to the management of patients with AIS since 2013. The purpose of these guidelines is to provide an up- to-date comprehensive set of recommendations for clinicians caring for adult patients with acute arterial ischemic stroke in a single document. These guidelines address prehospital care, ur- gent and emergency evaluation and treatment with intravenous (IV) and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are often begun during the initial hospitalization. We have restricted our recom- mendations to adults and to secondary prevention measures that are appropriately instituted within the first 2 weeks. 