Despite many advances in pharmacotherapy over the past half centurye, only a fraction of patients with Major Depressive Disorder (MDD) can achieve remission after the first or second trial of pharmacotherapy. Those who failed standard antidepressant treatment are termed as Treatment-Resistant Depression (TRD). Pharmacotherapy for TRD is more viable over past 15 years in part due to advances in clinical trials such as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) and the US Department of Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study. In general, optimizing pharmacotherapy consists of switching to different agents, combination with different antidepressants, or augmentation with different class of psychotropic medications, and the latter is preferred. Augmenting agents with strong evidence include Bupropion, Lithium, Triiodothyronine (T3), Aripiprazole, Brexpiprazole, Quetiapine, and Olanzapine in combination with Fluoxetine. Many works need to be done to further advance this field. These include (1) Establish agreement on a standardized, systematic, and feasible definition of TRD, (2) Establish safety and tolerability beyond acute treatment phase, (3) Establish individual psychosocial and neurobiological marks such as pharmacogenetic variance, and (4) Utilize multi-treatment modules such as combination of psychotherapy and pharmacotherapy in conjunction with brain stimulation therapy such as electroconvulsive therapy, vagus nerve stimulation and transcranial magnetic stimulation; as well as non-traditional therapy such as nutritional supplements, exercise and light therapy.