Drugs containing carboxylic acid moieties are associated with a range of toxicities, some related directly to their pharmacology and others to the metabolites that they produce on undergoing biotransformations that reduce biological activity and enhance excretion. The reactions involved in metabolism include a wide range of conjugations to the carboxylic acid moiety plus modifications to the spacers used to attach them to the main body of the drug. Here we provide a metabolic perspective on the biotransformations that have been found to occur with drugs that contain a carboxylic acid and discuss the potential of these to cause toxicity. Based on our current understanding of the metabolism of carboxylic acid-containing drugs we then consider approaches that may mitigate toxicity.