Mood disorders are more common in persons with medical illness than in the general population, and add to suffering, morbidity, and mortality. As to diagnosis, emotional states seen in the context of illness range from denial to bland indifference to “normal” sadness, to pathological anxiety and depressive or manic syndromes. Within this range fall both primary mood disorders and mood disorders secondary to the primary illness and its treatment.Treatment is complicated by difficulties with patient engagement and retention, limited clinical trial data, illness-related sensitivity to medications and alterations in drug metabolism, drug side effects, and drug interactions. Limited data are available about potentially valuable treatments such as exercise, transcranial magnetic stimulation, ketamine and psychedelics. Collaborative care models for depression treatment in medical settings are effective but demanding to implement and sustain. Special considerations apply to treatment of patients near the end of life and those requesting hastened death. Psychiatric treatment of the medically ill patient can evoke strong feelings in the treatment provider.