The parallel development of precise knowledge on NK cell receptors and on their function has considerably supported our understanding of the extension of their involvement during HIV-1 infection. The relevant reduction of NK cell function is dependent on well-described perturbations of their expression of specific receptors, leading not only to inhibition of their patrolling activity against invading pathogens, but also to alterations of their crosstalk with other cells of the immune system. With NK cell failure, boosted viral replication reduces immune surveillance towards opportunistic neoplasm and impaired control of adaptive responses prevails. NK cell function in human and animal models showing efficient control of disease progression may offer new insights in mechanisms underlying the protection from infectious disease.