While depression sometimes responds crisply to treatment, there are many cases where it is only somewhat responsive. This is more frequent than might be imagined. Most people with depression still have significant residual symptoms, even with medication dosed appropriately, and for a long enough period of time. And these residual symptoms can cause substantial distress and impairment. Ongoing feelings of sadness, lack of interest, poor energy and sleep, concentration problems, guilt, hopelessness, negativity, and pessimism, all part of the Major Depressive Syndrome, do not respond evenly to treatment, even if depression overall gets somewhat better. This has lead for the search for add-on medications to help depression treatments work better. Some of these treatments include drugs like lithium and thyroid hormone, and the newer agents Abilify and Rexulti. While these medications help some partial responders, many fail to respond even to these add-ons, so the search goes on. The neurobiology of depression involves aberrant electrical and chemical signaling amongst various neuronal circuits in the brain. Among these, those utilizing the neurotransmitters serotonin, dopamine, and norepinephrine figure prominently. However, it is increasingly evident that other systems, some yet unidentified, are involved as well. Candidate systems include the endogenous opioid, corticosteroid, and cannabinoid systems; and the “sigma” receptor system. Further, even antidepressants within a “class,” such as “selective serotonin reuptake inhibitors,” can have other actions, some yet unknown, outside of serotonin reuptake inhibition, that can affect efficacy. This is why some patients respond to being changed from one to another antidepressant within a class. But clearly, somehow recruiting other antidepressant mechanisms in the brain by development of agents targeting non-traditional pathways is required to manage treatment-resistant depression. Such agents are a focus of intense research interest. Given the current therapeutic technology, it is often necessary to combine antidepressants and augmentation agents as above to achieve response; rarely is there a remission. It is further necessary to identify and address other co-occurring psychiatric disorders that could affect the outcome of treatment, such as depression actually being part of bipolar disorder – indeed, this is one of the most common causes of failure of a depressive episode to respond to antidepressant therapy. Other common co-conditions include anxiety and panic disorders, and posttraumatic stress disorder (PTSD) – especially among female patients. In summary, treatment-resistant depression is common. Treatment helps, but rarely eventuates in remission. Non-traditional neuronal pathways likely underlie differential response to various antidepressants, contribute to treatment non-response, and are targets of novel therapeutic agents currently under investigation. Finally, it is important to identify and address co-occuring psychiatric disorders in any depressed patient, but especially those who are treatment-resistant.