“Treatment resistant depression (TRD)” is defined when a patient’s depression has failed to respond to two consecutive adequate trails of different antidepressants. This begs the question as to who or what is “resistant”. TRD focuses on non-response, does not take into account the equally challenging situations of lack of a sustained response or intolerance/contraindication/non-acceptance of treatment. “Difficult-to-treat depression (DTD)” is an alternative, more clinically orientated, concept of depression with poor outcomes. It describes depression that continues to cause a burden to the patient despite usual treatment efforts by the clinician. Most importantly, DTD is associated with a chronic, rather than acute, illness model of care. Key to this is holistic, individualised, management identifying factors that may contribute to the poor outcome and which may be tractable. While remission of symptoms is the primary goal of treatment, if this is difficult to achieve, the focus might more appropriately shift towards optimal management of residual symptoms and most importantly improvement in psychosocial functioning and quality of life. This presentation will discuss how to manage DTD systematically using the DTD model of care to optimize not only symptomatic improvement of patients, but also reducing risks of relapse and maximizing improvements in patient’s quality of life.