In this review, we describe the evolutionary process involved in the discovery of the selective 5-HT uptake inhibitor, fluoxetine, and summarize some of the large body of scientific research performed on fluoxetine in the 20 years since the first publication. The historical background of the proposed involvement of 5-HT in psychiatric disorders and the activity of tricyclic antidepressants in depression is reviewed. The effects of fluoxetine in various in vitro assays and in animal studies including receptor down-regulation, neurochemical and behavioral models are summarized. In addition, the clinical effectiveness of fluoxetine in depression and obsessive compulsive disorders and its potential use in other disorders are examined.