Interferons (IFNs) are potent biologic response modifiers with antiviral and antiproliferative effects. The successful clinical application of IFNs for the treatment of chronic viral infections and malignancies has resulted in improved quality and quantity of life for thousands of patients, and the number of new indications for IFN therapy continues to grow. However, the therapeutic effectiveness of IFNs, including IFN-alpha, is often compromised by a variety of dose-related side effects that can be dose limiting. These side effects include flu-like symptoms, fatigue, anorexia, and depression, which may be mild or severe. A better understanding of the mechanisms by which IFN-alpha causes these side effects will facilitate the development of effective strategies to lessen their effects on the patient's quality of life and allow the maximum therapeutic dose of IFN-alpha to be administered.