The introduction of fluoxetine as the first selective serotonin reuptake inhibitor (SSRI) approved in the United States, initially for the treatment of depression, represents an important advance in psychopharmacology and has been the catalyst for much subsequent basic and clinical research. Considerable evidence has demonstrated that fluoxetine, like other SSRIs, has a broad spectrum of clinical indications. There is a consensus, however, that the commercial success of fluoxetine (and subsequently marketed SSRIs) derived from its advantageous safety profile, which propelled SSRIs to dominance in the antidepressant drug market. Fluoxetine, under the brand name Prozac, became a cultural icon—a symbol of the growth in antidepressant prescribing and depression recognition. Consequently, it also became a focus of controversies about rare events attributed to side effects, such as violent acts and suicide, and a symbol of the medicalization of mental health concerns. Fluoxetine was also the first of the SSRI blockbuster drugs to become available in generic form; ironically, with decreased cost has come decreased market share, likely reflecting the reduction in marketing and availability of office samples. Although SSRIs, as a class, share several common features, individual agents, such as fluoxetine, also have unique characteristics.