A cute ischemic stroke (AIS) is a common disorder with almost 700 000 new or recurrent events per year in the United States. The risk of AIS varies by region, with the highest incidence occurring in the so-called stroke belt in the southern part of the country.1 The risk of AIS varies among African Americans, Latinos, and Caucasians, with the highest risk in African Americans. The risk of AIS increases with age, and the ageing of the US population portends an increase in AIS incidence and prevalence over the next several decades, despite increasingly effective efforts to treat stroke risk factors and the use of other preventive strategies.2 The incidence of AIS is also increasing in many other countries, largely related to potentially modifiable risk factors, especially in the developing world.3 The incidence of AIS is also greater among women beginning with an increased risk in the perimenopausal period and continuing into older age groups. Abstract: The treatment of acute ischemic stroke has undergone dramatic changes recently subsequent to the demonstrated efficacy of intra-arterial (IA) device-based therapy in multiple trials. The selection of patients for both intravenous and IA therapy is based on timely imaging with either computed tomography or magnetic resonance imaging, and if IA therapy is considered noninvasive, angiography with one of these modalities is necessary to document a large-vessel occlusion amenable for intervention. More advanced computed tomography and magnetic resonance imaging studies are available that can be used to identify a small ischemic core and ischemic penumbra, and this information will contribute increasingly in treatment decisions as the therapeutic time window is lengthened. Intravenous thrombolysis with tissue-type plasminogen activator remains the mainstay of acute stroke therapy within the initial 4.5 hours after stroke onset, despite the lack of Food and Drug Administration approval in the 3-to 4.5-hour time window. In patients with proximal, large-vessel occlusions, IA device-based treatment should be initiated in patients with small/moderate-sized ischemic cores who can be treated within 6 hours of stroke onset. The organization and implementation of regional stroke care systems will be needed to treat as many eligible patients as expeditiously as possible. Novel treatment paradigms can be envisioned combining neuroprotection with IA device treatment to potentially increase the number of patients who can be treated despite long transport times and to ameliorate the consequences of reperfusion injury. Acute stroke treatment has entered a golden age, and many additional advances can be anticipated. (Circ Res. 2017;120:541-558.