Due to the complexity of the disease, several hypotheses exist to explain the etiology of depression. The monoamine theory of depression suggests that disruptions in the serotonergic and noradrenergic systems result in depressive symptoms. Therefore, the serotonin transporter (SERT) has become a pharmacological target for treating these symptoms. This review will discuss what is known about the molecular interactions of antidepressants with SERT. The effects of antidepressants on SERT regulation and expression in addition to the receptors that may be involved in mediating these effects will be addressed. Specifically, how changes to SERT expression following chronic antidepressant treatment may contribute to the therapeutic benefits of antidepressants will be discussed. Furthermore, the effects of SERT gene polymorphisms on antidepressant efficacy will be examined. Finally, a brief overview of other hypotheses of depression will be addressed as well as factors that must be considered for future antidepressant development.