The effect on hepatic isoenzymes is emerging as the major clinically important distinguishing characteristic among the selective serotonin reuptake inhibitors (SSRIs). Although this fact has only recently gained widespread attention, the knowledge that some SSRIs inhibit hepatic metabolism dates back almost 20 years. This paper will first provide an overview of hepatic isoenzymes and then present the history and our current understanding of the effects of different SSRIs on different hepatic isoenzymes. Most of the attention in this area has focused on drug-drug interactions. This paper will also review recent work indicating that genetically determined differences in hepatic isoenzyme function can be risk factors in the development of a variety of diseases. The possible implications of this work relative to the long-term use of SSRIs will be discussed.