Natural killer (NK) cells represent a key component of the immune system that bridges innate and adaptive immunity. They play a central role in host immune defenses against viral pathogens by rapidly eradicating and clearing virally infected and transformed cells. In addition to their prompt cytotoxic activity during the early stages of infection, NK cells contribute to the coordination and amplification of the immune system through cytokines secretion and crosstalk with other immune cell populations. Chronic infection by the human immunodeficiency virus 1 (HIV-1) induces progressive functional exhaustion across multiple immune compartments, including NK cells. HIV-1 viremia pathologically disrupts NK cells homeostasis, impairing their cytotoxic functions and altering their regulatory features. Nonetheless, the upregulation of specific NK cell receptors and the activation of NK cell antibody-dependent cell cytotoxicity (ADCC) have been reported to control HIV-1 infection. Given the limited success of both T cell-dependent immunotherapy and broadly neutralizing antibodies (bNAbs) in achieving durable control of HIV-1 viremia, NK cell-based immunotherapy aims to successfully restore NK cells effectiveness and eradicate HIV reservoirs toward a functional cure for HIV. This chapter synthesizes our current knowledge on the impact of HIV-1 infection on NK cell biology, outlines the challenges associated with the development of anti-HIV-1 immunotherapy, and discusses the latest advances in NK cell-based therapies to control HIV-1 replication and reservoir persistence.