Fluoxetine continues to be remarkably successful; greater volumes of this drug are sold than for any other antidepressant in the world. Prozac has also become a household name. In this article we examine the circumstances that surround this success, and the evidence base that supports it. Rather than being a major step forward in the treatment for depression, the evidence for fluoxetine and for the selective serotonin reuptake inhibitors in general suggest at best a modest improvement in tolerability, with no evidence of improved efficacy. We note that the road to success was not problem free for fluoxetine, and highlight the response of the sponsor in the development of subsequent drugs for CNS disorders.