Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities. Members of diverse drug classes undermine mitochondrial function, and among the most potent are drugs that have been withdrawn from the market, or have received Black Box warnings from the FDA. To avoid mitochondrial liabilities, routine screens need to be positioned within the drug-development process. Assays for mitochondrial function, cell models that better report mitochondrial impairment, and new animal models that more faithfully reflect clinical manifestations of mitochondrial dysfunction are discussed in the context of how such data can reduce late stage attrition of drug candidates and can yield safer drugs in the future.