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Acetaminophen poisoning is the most common cause of medication overdose death in the United States. While most patients can be safely managed outside the ICU, serious toxicity can result in hepatic failure and death. N-acetylcysteine has been shown to prevent liver injury when administered early and reduce mortality for patients with hepatic failure. The proposed mechanism of acetaminophen toxicity and N-acetylcysteine therapy are discussed, as well as extra-hepatic toxicity of acetaminophen. Other topics that are discussed include the interaction of ethanol consumption and acetaminophen toxicity and recent advances in the management of acetaminophen poisoning.