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Its application has broadened across a wide spectrum of critical illness, yet the mechanistic basis of its physiologic benefit remains incompletely defined. This review explores the mechanisms through which extracorporeal life support may confer benefit in respiratory and cardiac failure. These include restoration of gas exchange, optimization of circulatory dynamics, and mitigation of secondary organ injuries, creating conditions that facilitate tissue repair, enable adjunctive therapies, and, in selected cases, provide a bridge to transplantation. In isolated respiratory failure, respiratory extracorporeal life support stabilizes gas exchange and modulates respiratory drive, enabling lung-protective ventilation and potentially attenuating ventilator- and patient self-inflicted lung injury. In cardiogenic shock, cardiac extracorporeal life support restores systemic perfusion and may reduce myocardial oxygen demand, while during cardiac arrest, it may confer neuroprotective effects. In combined cardiorespiratory failure, advanced extracorporeal support modalities may augment both systemic and pulmonary circulation, supporting gas exchange and maintaining end-organ perfusion. Mechanistically, these interventions interrupt the cascade of hypoxemia- and\/or hypercapnia- induced pulmonary vasoconstriction, right ventricular overload, and systemic hypoperfusion, facilitating multiorgan recovery. Optimizing patient selection, timing for extracorporeal life support initiation, and use of adjunctive therapies require a nuanced understanding of the interplay between these physiologic pathways alongside careful considerations of key limitations, including device-related complications, hematologic and inflammatory perturbations, and physiologic trade-offs. This State-of-the-Art review synthesizes the current literature on the mechanistic basis of extracorporeal life support in adults.<\/jats:p>","DOI":"10.1093\/ajrccm\/aamag321","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T11:53:45Z","timestamp":1781870025000},"page":"2159-2174","source":"Crossref","is-referenced-by-count":0,"title":["Extracorporeal life support in adult critically ill patients: mechanisms of benefit in respiratory and cardiac failure"],"prefix":"10.1093","volume":"212","author":[{"given":"Vasileios","family":"Zochios","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Critical Care Medicine and ECMO Unit, Glenfield Hospital, University Hospitals of Leicester NHS Trust , Leicester,","place":["United Kingdom"]},{"name":"Department of Cardiovascular Sciences, University of Leicester , Leicester,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph 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