The neurosurgical treatment of treatment-resistant depression (TRD) has entered a new era with more and more patients being treated with deep brain stimulation (DBS) via surgically implanted intracerebral electrodes. Although the mechanisms of action of DBS are still not fully understood, preclinical studies are being conducted to elucidate how the treatment might work. DBS in its present form can be considered as a relatively new neurosurgical treatment for TRD. However, the use of neurosurgery in the management of depression has a much longer history particularly with ablative procedures but also vagal nerve stimulation. Here, we provide a review of the clinical neurosurgical treatments for TRD, with a main emphasis on DBS. In addition, we discuss relevant preclinical data that are revealing new information about DBS mechanisms.