INTRODUCTION. Worldwide, diabetes mellitus and depression are among the most prevalent diseases in their respective fields, metabolism and psychiatry. However, there is evidence that patients with diabetes are at increased risk of developing depression, although a bidirectional relationship might also exist. AIM. To present a comprehensive review of the clinical, epidemiological, psychosocial, emotional, and neurobiological basis of the relation between diabetes and depression. DEVELOPMENT. Epidemiological studies indicate that there is not only an augmented risk of developing depression in diabetic patients, but that this association increases the morbidity and mortality of these patients. While there is a considerable number of clinical studies that support this relation, little is known about the neurochemical mechanisms that would constitute its biological basis. CONCLUSION. Alterations in monoamines (serotonin and noradrenaline), the increases in cortisol by the hypothalamus-pituitary-adrenal axis, and trophic agents such as the brain-derived neurotrophic factor, through glycogen synthase kinase-3, constitute some of the abnormalities documented in diabetic patients and in animal models that could explain the association between depression and diabetes. Additionally, we briefly consider the psychoemotional factors that might underlie the depression-diabetes relation. The effects (most of them deleterious) of the antidepressive therapy in glucometabolic control are also discussed.