Depression in the medically ill is a common clinical problem that primary physicians and psychiatric consultants encounter. Treatment of such patients begins with a careful evaluation of the patient's medical and psychiatric conditions. The assessment of depression in the medical patients requires a multidimensional approach. Psychological instruments are also used as a method of assessment in these patients. First of all, what the therapists have to do is to find and remove organic causes. Psychosoical treatment includes dealing with the patient's resistance and despondency relevant to physical diseases. For biological treatment, it is important to select appropriate antidepressants. Therapists should be familiar with the side effects of the antidepressants as well as the patient's primary depressive symptoms, pharmacokinetics and pharmacodynamics of the available agents. In addition, special attention should be paid to the potential for drug-illness and drug-drug interactions. Tricyclic antidepressants can be still effectively used for patients with pain disorder, although a variety of new antidepressants such as selective serotonin reuptake inhibitors (SSRI), bupropion and venlafaxine could have more benefits in depression of the medically ill. However, electroconvulsive therapy can be recommended for refractory cases of depression in patients with medical illness.