Following the discovery of innate immune receptors, the topics of innate immunity and its role in defense against infective agents have recently blossomed into very active research fields, after several decades of neglect. Among innate immune cells, natural killer (NK) cells are endowed with the unique ability to recognize and kill cells infected with a variety of pathogens, irrespective of prior sensitization to these microbes. NK cells have a number of other functions, including cytokine production and immunoregulatory activities. Major advances have recently been made in the understanding of the role of NK cells in the physiopathology of infectious diseases. The cellular and molecular mechanisms regulating the acquisition of effector functions by NK cells and their triggering upon pathogenic encounters are being unraveled. The possibility that the power of NK cells could be harnessed for the design of innovative treatments against infections is a major incentive for biologists to further explore NK cell subset complexity and to identify the ligands that activate NK cell receptors.