Interferon (IFN) is a pro-inflammatory cytokine that is widely used for the treatment of a number of disorders including viral infections, hematological proliferative disorders, and skin malignancies. Unfortunately, IFN frequently induced depression and has led to compromised tolerability with lowering of the dose of IFN and even discontinuation of treatment. Thus, it is imperative to diagnose IFN-induced depression early, evaluate whether this depression is associated with IFN-induced anemia or thyroid dysfunction, which can be corrected, and if necessary treat with antidepressants. IFN-induced depression is highly responsive to antidepressants with benefits occurring frequently at relatively low doses and after only a few weeks. Although SSRIs have mainly been studied, non-SSRIs appear to be effective also. Antidepressants have a number of risks and side effects that must be considered and may enter into the decision as to which antidepressant to choose. If IFN induces a depression in a patient with a bipolar disorder history, antidepressant treatment must include a mood stabilizer. In the case of vulnerable patients (e.g., those who have significant depressive symptoms prior to IFN or who have had an IFN-induced depression in the past) prophylactic antidepressant treatment appears to decrease the likelihood of having an IFN-induced depression. On the basis of known and effective treatment strategies, IFN-induced depression should not be an obstacle for continued treatment in most patient populations.