Effective antidepressants include monoamine oxidase inhibitors and tricyclic antidepressants, selective serotonin re-uptake inhibitors and novel agents, including serotonin and noradrenaline re-uptake inhibitors. Although effective, current treatments most often produce partial symptomatic improvement (response) rather than symptom resolution and optimal functioning (remission). While current pharmacotherapies target monoaminergic systems, different symptoms of major depressive disorder (MDD) may have distinct neurobiological underpinnings and other neurobiological systems are likely involved in the pathogenesis of MDD. In this article a review of current pharmacotherapeutic options for MDD, current understanding of the neurobiology and pathogenesis of MDD and a review of new and promising directions in pharmacological research will be provided. It is generally accepted that no single neurotransmitter or system is responsible for the dysregulation found in MDD. While agents that affect monoaminergic systems will likely continue to be first-line treatments for MDD for the foreseeable future, a number of new and novel agents, including corticotropin-releasing factor antagonists, substance P antagonists and antiglucocorticoids show considerable promise for refining treatment options. In order to better understand the neurobiology and treatment response of MDD, it is probable that more sophisticated theory-driven typologies of MDD will have to be developed.