Interferons, induced early during viral infections, represent important regulators of both innate and adaptive immune responses, and provide protective effects against a wide range of pathogens, including HIV. Several in vitro studies and some in vivo data from HIV-exposed seronegative cohorts indicate that interferons and interferon-mediated immune responses are crucial in preventing early HIV replication. Following establishment of HIV infection, the uncontrolled (aberrant) activation of the immune system, in part regulated by interferon levels, contributes to HIV-1-induced immune activation and disease progression. Modulation of interferon responses prior to and during HIV infection shows promise for development of novel therapeutics to prevent HIV transmission, clear HIV infection, and dampen chronic immune activation. In this review we discuss the role that interferons play in protection from HIV infection, acute infection, and their role in HIV pathogenesis and disease progression. Lastly, we review recent advances in modulating interferon responses for purposes of developing novel HIV therapeutic approaches.(AIDS Rev. 2014; 16: 43-52)