Two forms of recombinant interferon-alpha (IFN-alpha2a and IFN-alpha2b) have been approved by the Food and Drug Administration for a variety of clinical indications, including hairy cell leukemia, hepatitis, acquired immunodeficiency syndrome-related Kaposi's sarcoma, chronic myelogenous leukemia (IFN-alpha2a only), and adjuvant therapy for melanoma (IFN-alpha2b only), based on their proven clinical efficacy and acceptable safety profiles. The continued postmarketing monitoring of adverse reactions associated with IFN-alpha therapy has revealed some new toxicities. The most common adverse events associated with IFN-alpha therapy are flu-like symptoms, fatigue, anorexia, and central nervous system and psychiatric reactions. In particular, the incidence of depression has only recently been fully appreciated. Some of these side effects, particularly chronic fatigue, anorexia, and neuropsychiatric reactions, may become dose limiting. New approaches to minimize and manage the side effects of IFN-alpha therapy are needed.