Nearly all analgesic and anti-inflammatory agents have the potential for hepatic injury. Most nonsteroidal anti-inflammatory drugs (NSAIDs) produce injury in an unpredictable fashion by way of an idiosyncratic (immunologic versus metabolic) mechanism, whereas acetaminophen and aspirin are more predictable because they produce injury in a dose-dependent manner by way of intrinsic toxicity. Both acetaminophen and aspirin may produce hepatotoxicity despite therapeutic intent. This article discusses specific NSAIDs available in the United States and abroad and their associated hepatotoxicity and carefully considers acetaminophen-related hepatotoxicity reviewing risk factors for injury, clinical features, prognosis, and management.