Type 1 interferons (IFN-α/β) are a major first line of host defense against viral infection. Because of this potent antiviral activity, IFN-based therapies have been developed for chronic infections with hepatitis B and C viruses, as well as for HIV. However, a poorly understood phenomenon has been the persistence of virus despite induction of antiviral immune responses by type 1 IFNs. On page 207 and 202 in this issue, Teijaro et al. and Wilson et al. address this long-standing question and find that IFN-α/β can also suppress the immune system in ways that promote viral persistence. This paradoxical finding should spur a reassessment of the fundamental roles of IFN-α/β during chronic infections.