: Natural killer (NK) cells are important effectors of innate immunity playing a key role in the eradication and clearance of viral infections. Over the recent years, several studies have shown that HIV-1 pathologically changes NK cell homeostasis and hampers their antiviral effector functions. Moreover, high levels of chronic HIV-1 viremia markedly impair those NK cell regulatory features that normally regulate the cross talks between innate and adaptive immune responses. These pathogenic events take place early in the infection and are associated with a pathologic redistribution of NK cell subsets that includes the expansion of anergic CD56/CD16 NK cells with an aberrant repertoire of activating and inhibitory receptors. Nevertheless, the presence of specific haplotypes for NK cell receptors and the engagement of NK cell antibody-dependent cell cytotocity have been reported to control HIV-1 infection. This dichotomy can be extremely useful to both predict the clinical outcome of the infection and to develop alternative antiviral pharmacological approaches. Indeed, the administration of antiretroviral therapy in HIV-1-infected patients restores NK cell phenotype and functions to normal levels. Thus, antiretroviral therapy can help to develop NK cell-directed therapeutic strategies that include the use of broadly neutralizing antibodies and toll-like receptor agonists. The present review discusses how our current knowledge of NK cell pathophysiology in HIV-1 infection is being translated both in experimental and clinical trials aimed at controlling the infection and disease.