For treatment of depression in the medically ill, addressing underlying organic causes is paramount. Therapists should address patients’ resistance to psychiatric approach and depressive reaction to severe physical illness. It is important to choose appropriate antidepressants as a biological treatment. Therapists also need to pay attention to drug-disease and drug-drug interactions. Antidepressants, such as SSRIs, bupropion, and venlafaxine, are effective in treating depression in medically ill patients. However, tricyclic antidepressants can still be effectively used for patients experiencing pain. The psychosocial approach for medically ill patients with depression should be supportive, allowing them to ventilate their emotions, minimizing injury to self-esteem, and fostering hope. Therapeutic staff, including physicians, should engage patients with warmth and partnership as consultants, avoiding authoritarian attitudes. Even when physical recovery is limited, it should be emphasized that psychological recovery remains possible. Clinicians’ therapeutic approaches should be tailored to the specific needs of patients from a biopsychosociospiritual perspective.