Viruses and hosts are involved in a continuing ‘arms race’. The body deploys multiple defenses; however, viruses utilize generally superior and more rapidly evolving tactics for negating host immune surveillance and viral clearance. In the case of the two major pathogenic human retroviruses, human immunodeficiency virus-1 (HIV-1) and human T-lymphotrophic virus-I (HTLV-I), the nuclear factor-κB (NF-κB) transcription factor plays a key role in the host’s anti-viral responses involving both the innate and adaptive arms of the immune response. Similarly, these retroviruses capably exploit NF-κB for their replication, spread, and pathogenic functions. In this review, we discuss the dynamic and intimate interplay that occurs between NF-κB and the HTLV-I and HIV-1 retroviral pathogens.