Cohort studies indicate a high prevalence of depression in patients with diabetes mellitus. Despite numerous investigations, the underlying pathophysiologies of the metabolic abnormalities are poorly understood. A possible role play the increased counter-regulatory hormone release involved in glucose homeostasis, alterations in the glucose transport function and increased inflammatory activation triggered by depression. The diagnose of "depression" in diabetic patients might be hampered by similar symptoms of both conditions as fatigue, psychomotor inhibition, reduced appetite or sexual dysfunction. In treating depressive patients with diabetes one should consider potential induction or worsening of diabetes-like metabolic alterations. Selective serotonin-reuptake-inhibitors, venlafaxin and MAO-Inhibitors constitute a beneficial choice. Atypical antipsychotics like clozapine, olanzapine, quetiapine and risperidone should be given with precaution due to potential effects on glucose homeostasis.