ART-related hepatotoxicity can manifest in a variety of ways. Although benign, asymptomatic LEEs predominate, liver injury occurring in the context of either hypersensitivity or hyperlactatemia, represents a medical emergency and mandates immediate cessation of ART. Underpinning this broad spectrum of presentations are several, as yet poorly understood, mechanisms of liver damage that reflect contributions by constituents of HAART and host factors. Thus far, the most significant predisposing condition to emerge from clinical studies is chronic viral hepatitis. A more precise understanding, however, of the processes and factors that underlie ART-related hepatotoxicity is critical not only to the management of liver injury from current antiretroviral drugs but also to the design of safer drugs in the future.