Given the profound negative public health effects of major depressive disorder (MDD), and data suggesting only modest effectiveness of existing psychological and pharmacological treatments for this condition, there has been increasing interest in exploring the antidepressant potential of non-pharmacological, brain-based interventions, such as deep brain stimulation (DBS). The use of the DBS for psychiatric indications follows a decade of data suggesting that DBS is an effective, evidence-based strategy for the treatment of movement disorders such as Parkinson's disease. At the present time there is open-label case series data to suggest that DBS in the subgenual cingulate gyrus, ventral caudate/ventral striatum, and the nucleus accumbens, is associated with antidepressant effects in individuals who fail to respond to conventional treatments for MDD. However a number of unresolved issues about the optimal use of DBS for MDD remain, such as the optimal anatomical placement of the electrodes and the mechanisms of its antidepressant effects. This review summarizes the clinical experience of DBS for treatment resistant depression (TRD). The rationale for the use of DBS for TRD is reviewed in the context of the growing neuroimaging literatures exploring the biomarkers of antidepressant response, and the neural substrates of emotional regulation in both normal and pathological states.