Adjuvant interferon-alpha (IFN-alpha) therapy in patients with melanoma has been established as standard therapy since more than 10 years.During IFN-alpha therapy, flu-like symptoms, gastrointestinal disorders, arthralgias and neuropsychiatric symptoms are the most common side effects. The management and prophylaxis of these side effects have been improved by a more detailed understanding of pathophysiologic mechanisms and increased clinical experience. New insights in the relevance of detection of autoantibodies and development of autoimmunity have influenced the clinical pathway substantially. This review covers the pathomechanisms, incidence and optimized therapy of IFN-alpha-associated side effects.