Abstract: Major depressive disorder (MDD) is a common psychiatric condition characterized by two main symptoms, low mood and anhedonia. About 15–30% of people suffering from MDD do not respond to standard-of-care antidepressants, e.g., the serotonin re-uptake inhibitors (SSRI), and are considered affected by Treatment-Resistant Depression (TRD). The neurobiology of this condition is presently unknown. Recent attempts of developing novel treatments for TRD have been driven by four major breakthroughs: (1) Increasing dopaminergic neurotransmission improves TRD symptoms; (2) Anhedonia occurs when central dopaminergic neurotransmission is low; (3) Enhanced neuroplasticity is critical for the action of antidepressants; (4) Ketamine shows antidepressant properties in TRD patients and triggers neuroplasticity in preclinical animal models. These breakthroughs are at the basis of a putative human translational cellular model for antidepressant agents that we are proposing in this article. The rationale is briefly described here.