Extracorporeal membrane oxygenation (ECMO) has been used with increasing frequency to support patients with acute respiratory failure, most commonly, and severe forms of acute respiratory distress syndrome (ARDS). The marked increase in the global use of ECMO followed the publication of a large randomized trial in 2009 and the experience garnered during the 2009 influenza A (H1N1) pandemic, and has been further supported by the release of a large, randomized clinical trial in 2018, confirming a benefit from using ECMO in patients with severe ARDS. Despite a rapid expansion of ECMO-related publications, optimal management of patients receiving ECMO, in terms of patient selection, ventilator management, anticoagulation, and transfusion strategies, is evolving. Most recently, ECMO is being utilized for an expanding variety of conditions, including for cases of severe pulmonary or cardiac failure from coronavirus disease 2019 (COVID-19). This review evaluates modern evidence for ECMO for respiratory failure and the current challenges in the field.