The therapeutic margin for any drug is based on both toxicity and efficacy. Generally, toxicity is dose-dependent and is driven either by the therapeutic target or by an untoward target. However, idiosyncratic toxicities are usually not observed until a drug has been on the market and has gained broad exposure. Except in the case of pharmacokinetic interactions, these toxicities are not driven solely by drug exposure but rather depend on several drug- and patient-related risk factors. Drug-related risk factors include metabolism, bioactivation and covalent binding, and the inhibition of key cell functions. Patient-related risk factors include underlying disease, age, gender, comedications, nutritional status, activation of the innate immune system, physical activity, and genetic predispositions. Idiosyncratic toxicity can occur when a convergence of risk factors, including drug exposure, tips the risk-benefit balance away from benefit and toward risk.