Interferon alpha (IFNalpha) is used for the treatment of several disorders, such as chronic hepatitis or malignant melanoma. During the therapy, IFNalpha 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. Our aim is to review research evidence for the contribution of IFNalpha for the etiopathology of psychiatric syndromes. Therefore, research findings of neuropsychiatric syndromes induced by IFNalpha treatment, the putative mechanisms underlying those syndromes, and their treatment are-reviewed. Furthermore, neuropsychiatric syndromes in diseases with high IFNalpha levels such as systemic lupus erythematosus (SLE) are discussed. Finally, the question is addressed whether IFNalpha may contribute to the etiopathology of endogenous psychiatric disorders. IFNalpha may cause psychiatric syndromes in a subset of treated patients. The underlying pathogenetic mechanisms include various effects on neuroendocrine, cytokine, and neurotransmitter systems. Research data on the role of IFNalpha in the pathogenesis of endogenous psychiatric disorders are conflicting. Future research should improve our understanding of the role of IFNalpha for the etiopathology of psychiatric syndromes and has an impact on treatment of IFNalpha-induced psychiatric syndromes.