Depression is one of the most common comorbidities of many chronic medical diseases including cancer and cardiovascular, metabolic, inflammatory and neurological disorders. Indeed, the prevalence of depression in these patient groups is often substantially higher than in the general population, and depression accounts for a substantial part of the psychosocial burden of these disorders. Many factors can contribute to the occurrence of comorbid depression, such as shared genetic factors, converging biological pathways, social factors, health behaviours and psychological factors. Diagnosis of depression in patients with a medical disorder can be particularly challenging owing to symptomatic overlap. Although pharmacological and psychological treatments can be effective, adjustments may need to be made for patients with a comorbid medical disorder. In addition, symptoms or treatments of medical disorders may interfere with the treatment of depression. Conversely, symptoms of depression may decrease adherence to treatment of both disorders. Thus, comprehensive treatment plans are necessary to optimize care.