Metabolism represents the most prevalent mechanism for drug clearance. Many drugs are converted to metabolites that can retain the intrinsic affinity of the parent drug for the pharmacological target. Drug metabolism redox reactions such as heteroatom dealkylations, hydroxylations, heteroatom oxygenations, reductions, and dehydrogenations can yield active metabolites, and in rare cases even conjugation reactions can yield an active metabolite. To understand the contribution of an active metabolite to efficacy relative to the contribution of the parent drug, the target affinity, functional activity, plasma protein binding, membrane permeability, and pharmacokinetics of the active metabolite and parent drug must be known. Underlying pharmacokinetic principles and clearance concepts are used to describe the dispositional behavior of metabolites in vivo. A method to rapidly identify active metabolites in drug research is described. Finally, over 100 examples of drugs with active metabolites are discussed with regard to the importance of the metabolite(s) in efficacy and safety.