Acetaminophen (APAP) overdose remains one of the most common causes of acute liver failure in the United States. While its therapeutic use is widespread and generally safe, unintentional overdoses and delayed presentations can lead to devastating outcomes. In this episode of REBEL Cast, Swami breaks down the pathophysiology, clinical course, diagnostic approach, and evidence-based management of APAP toxicity—including when to initiate NAC, how to apply the Rumack-Matthew nomogram, and the evolving role of adjunctive therapies like fomepizole. Whether you're in the ED or elsewhere , this is core content every clinician should know.