The formation of drug-protein adducts is considered an important feature in the pharmacological and toxicological profiles of many drugs. Mechanistic insights into the role of specific protein adduct formation in pharmacology and toxicology remain scarce, partly due to the availability of tools to identify and characterize the specific protein adducts, and partly due to the scarcity of relevant in vitro and in vivo predictive models. This review serves to provide a review on the current state of science on the chemistry, toxicology, and methods of detection and characterization of drug-protein adducts and to offer some perspective on the future directions of research into the role of protein adducts in drug effects and toxicity.