In this chapter, drug-metabolizing enzymes known to play key roles in the enhancement of drug toxicity via metabolic activation, and in the reduction of drug toxicity via metabolic detoxification, as well as toxic drug–drug interactions are reviewed. The drug-metabolizing enzymes reviewed include both P450 and non-P450 pathways. Each pathway is reviewed in terms of substrates, inducers, inhibitors, individual variations, and involvement in drug toxicity.