Interferon alpha (IFN-alpha) is a cytokine that is widely used for the treatment of chronic viral infection or malignant disorders. During treatment with IFN-alpha, severe neuropsychiatric syndromes may occur such as depression with suicidal ideation, paranoid psychoses or confusional states. The neurobiological correlates of these side effects are widely unknown. Besides induction of other cytokines and hormonal changes, IFN-alpha has been shown to modulate the opioid, serotonin, dopamine and glutamate neurotransmitter system. Positive therapeutic effects of antidepressants such as selective serotonin-reuptake-inhibitors (SSRI) or of opioid receptor antagonists support the hypothesis that neurotransmitter changes play an important role in the development of IFN-alpha associated neuropsychiatric side effects. We review recent research about IFN-associated neurotransmitter changes in the central nervous system and discuss treatment strategies.