Several emerging treatment options for depression have shown promise, especially for patients resistant to treatment with first-line drugs. Described in this chapter are a variety of options that may assist in treating depression, whether as a monotherapy or in combination with another drug of choice. The concept of trimonoamine modulators (TMMs) is introduced to explain the actions of many agents used to augment anti-depressants including lithium, thyroid, and L-methylfolate. Estrogen as a TMM is explained in the following chapter. Various forms of brain stimulation/neuromodulation are also illustrated here, from vagus nerve stimulation (VNS) to transcranial magnetic stimulation (TMS) to deep brain stimulation (DBS). A few new therapeutic approaches to the treatment of depression are also included at the end of the chapter.