There have been significant advances in the treatment of depression since the serendipitous discovery that modulating monoaminergic neurotransmission may be a pathological underpinning of the disease. Despite these advances, particularly over the last 15years with the introduction of selective serotonin and/or norepinephrine reuptake inhibitors (SNRI), there still remain multiple unmet clinical needs that would represent substantial improvements to current treatment regimens. In terms of efficacy there have been improvements in the percentage of patients achieving remission but this can still be dramatically improved and, in fact, issues still remain with relapse. Furthermore, advances are still required in terms of improving the onset of efficacy as well as addressing the large proportion of patients who remain treatment resistant. While this is not well understood, collective research in the area suggests the disease is heterogeneous in terms of the multiple parameters related to etiology, pathology and response to pharmacological agents. In addition to efficacy further therapeutic advances will also need to address such issues as cognitive impairment, pain, sexual dysfunction, nausea and emesis, weight gain and potential cardiovascular effects. With these unmet needs in mind, the next generation of antidepressants will need to differentiate themselves from the current array of therapeutics for depression. There are multiple strategies for addressing unmet needs that are currently being investigated. These range from combination monoaminergic approaches to subtype selective agents to novel targets that include mechanisms to modulate neuropeptides and excitatory amino acids (EAA). This review will discuss the many facets of differentiation and potential strategies for the development of novel antidepressants.