Depressive disorders are common conditions that place a large burden of illness on patients, employers, payers, and society. Although efficacious interventions exist to treat various forms of the condition, substantial gaps in care remain. The selective serotonin re-uptake inhibitors (SSRIs) represent the most commonly utilized drug class for the treatment of depression; sertraline is the most prescribed single agent and received generic drug approval in 2006. The results of pharmacoeconomic analyses comparing the costs and outcomes of sertraline with other antidepressants are mixed; in particular, investigations emphasize branded medications relative to costs. Continued research is needed to support decision making given recent changes in the antidepressant marketplace, particularly the introduction of generic sertraline and newer agents, and the complexity that surrounds the management of depressive disorders.