Many xenobiotics are metabolically activated to electrophilic intermediates that form covalent adducts with proteins; the mechanism of toxicity is either intrinsic or idiosyncratic in nature. Many intrinsic toxins covalently modify cellular proteins and somehow initiate a sequence of events that leads to toxicity. Major protein adducts of several intrinsic toxins have been identified and demonstrate significant decreases in enzymatic activity. The reactivity of intermediates and subcellular localization of major targets may be important in the toxicity. Idiosyncratic toxicities are mediated through either a metabolic or immune-mediated mechanism. Xenobiotics that cause hypersensitivity/autoimmunity appear to have a limited number of protein targets, which are localized within the subcellular fraction where the electrophile is produced, are highly substituted, and are accessible to the immune system. Metabolic idiosyncratic toxins appear to have limited targets and are localized within a specific subcellular fraction. Identification of protein targets has given us insights into mechanisms of xenobiotic toxicity.