NK cells are critical effector cells of the innate immune response to malignancy and infection. These cells have a wide array of direct antiviral activities and have been critically implicated in the regulation and induction of an effective adaptive immune response. Although the pivotal role of this cell subset in the context of a number of viral infections is well established, the role of NK cells in HIV-1 infection is less well understood. Recent data has demonstrated the association between an NK cell receptor, KIR3DS1, and its ligand, HLA-Bw4 with an isoleucine at position 80, and slower disease progression. This data suggests that NK cells may play an essential role in the control of HIV-1 disease, and has provided the impetus to begin to better understand the role of this cell subset in the context of HIV-1 infection, replication, and pathogenesis. Here we present a review of the literature pertaining to both the effect of HIV-1 infection on NK cell activity and the potential role that this subset of cells may play in controlling HIV-1 disease.