Interferon alpha (IFN-alpha), an immunomodulatory cytokine, is used for the treatment of several disorders including chronic hepatitis or malignant melanoma. During the therapy IFN-alpha may cause severe neuropsychiatric syndromes including depression with suicidal ideation, paranoid psychoses or confusional states. The reasons and management of these side effects are widely unknown. The underlying pathogenetic mechanisms include various effects on neuroendocrine, cytokine and neurotransmitter systems. This review summarizes therapeutic strategies against IFN-alpha associated psychiatric syndromes. Zolpidem or Zopiclon can be used for the treatment of sleeping disturbances. Serotonin-reuptake-inhibitors including citalopram or paroxetine were shown to be effective for acute treatment of IFN-alpha associated depression. The efficacy of prophylactic treatment for prevention of IFN-alpha induced depression has to be proven in future trials. In an interdisciplinary setting, psychiatric disorders and drug addiction should not prevent patients from interferon-alpha treatment. Furthermore, interdisciplinary care should improve quality of life, adherence and therapeutic outcome of interferon-alpha treated patients.