The clinical significance of comorbid mental disorders and metabolic diseases, such as obesity, metabolic syndrome (MetS), and diabetes, depends on their high prevalence and combined negative effects on the patient’s well-being, treatment adherence and efficacy, and long-term outcomes. Such mental disorders as depression, eating disorders, and psychoses significantly increase mortality in diabetes. There is an emerging evidence on the bilateral association and impact between obesity, MetS, and diabetes, from one side, and mental disorders, from the other, such as affective and anxiety disorders, schizophrenia and bipolar disorder, posttraumatic stress disorder, etc. This association can be only partially explained by social problems met by people with mental disorders and side effects of psychopharmacological agents. More important could be a number of common neurophysiological, neuroendocrine abnormalities, and genetic factors. Both mental disorders in patients with metabolic diseases and metabolic disturbances in patients with mental disorders commonly remain underdiagnosed and undertreated. Comorbid metabolic and mental illness can be challenging for their differential diagnosis and management. A huge proportion of “brittle diabetes” is caused by comorbid mental disorders. The aim of this chapter is to increase awareness of this comorbidity among all healthcare providers working in both mental and medical care.