Determination of the chemical structures of metabolites is a critical part of the early pharmaceutical discovery process. Understanding the structures of metabolites is useful both for optimizing the metabolic stability of a drug as well as rationalizing the drug safety profile. This review describes the current state of the art in this endeavor. The likely outcome of metabolism is first predicted by comparison to the literature. Then metabolites are synthesized in a variety of in vitro systems. The various approaches to LC/UV/MS are applied to learn information about these metabolites and structure hypotheses are made. Structures are confirmed by synthesis or NMR. The special topic of reactive metabolite structure determination is briefly addressed.