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Treatment Refractory Depression (TRD) is a very common clinical problem. This paper will review the various definitions of TRD and give an account of the major concepts underlying this clinical syndrome. Recent evidence from a number of large European cohorts which have investigated the clinical features and psychosocial and psychological underpinnings of TRD will be discussed. Results from a large study of TRD patients carried out by our group will also be presented. We showed that the TRD patients had increased rates of childhood physical neglect, childhood emotional abuse, increased ruminations and neuroticism and each of these factors were associated with higher baseline depression scores. Childhood trauma and ruminations were associated with discrepancies on depression rating scales that were in turn related to outcome. The implication of these findings for clinical care and future research will be explored. While the phenotype is very complex there have been some advances made in understanding the underlying neurobiology of this disorder which will be reviewed. Dysregulation of the hypothalamic pituitary adrenal axis is common in such patients and the impact of this on cognition and response to treatment will be outlined. Our group have carried out two recent large studies looking at the impact of anti glucocorticoid therapy on the outcome of TRD. Addition of a GR receptor antagonist to antidepressants in bipolar TRD improved cognition but not clinical outcome and a similar pattern of results was seen in unipolar TRD with a cortisol synthesis inhibitor. The implications of these findings will be discussed. Recent research has also shown changes in the integrity of white matter in affective disorders and the impact of this on clinical features, cognition and response to treatment will be discussed. The paper will finish with a synopsis of the main treatment modalities for TRD including a review of recent advances in psychopharmacology in this area. There has also been a recent welcome interest in intensive psychotherapy for this condition and the results of such studies will also be discussed.