Type I interferons (IFN), which are immediately induced after most virus infections, are central for direct antiviral immunity and link innate and adaptive immune responses. After induction, they bind to their IFNα/β receptor, which leads to downstream signalling resulting in the expression of numerous differ-ent IFN-stimulated genes. These genes encode anti-viral proteins that directly inhibit viral replication and modulate immune function. Thus, the induction of type I IFN is a very powerful tool of the host to fight virus infections. However, several viruses have evolved strategies to evade the IFN response by prevent-ing IFN induction or blocking IFN signalling pathways. Therapeutic application of exogenous type I IFN is thus a significant option for future immunotherapies against chronic viral infections. An important part of the type I IFN family are 12 IFNαsubtypes, which all bind to the same receptor but differ significantly in their biological activities. To date, only one IFNα subtype (IFNα2) is being used in clinical treatment against chronic virus infections such as hepatitis B; however, its thera-peutic success rate is rather limited. Various clinical studies with human IFNα2 demonstrated no or modest beneficial therapeutic effects during human immunodeficiency virus (HIV) infection. Recent studies by our group addressed the important question of whether other IFNαsubtypes would be more potent against retroviral or hepadnaviral infections in in vitro and in vivoexperiments. Indeed, very potent IFNα subtypes were defined and their antiviral and immunomodu-latory properties characterized. The findings demonstrate the non-redundant role of the different IFNαsubtypes in viral infections, and the characterization of the mechanisms underlying the IFN response might help us to develop novel strategies for future immunotherapies against chronic viral infections.