Human natural killer (NK) cells are innate lymphoid cells that mediate important effector functions in the control of viral infection and malignancy. Their ability to distinguish "self" from "nonself" and lyse virally infected and tumorigenic cells through germline-encoded receptors makes them important players in maintaining human health and a powerful tool for immunotherapeutic applications and fighting disease. This review introduces our current understanding of NK cell biology, including key facets of NK cell differentiation and the acquisition and execution of NK cell effector function. Further, it addresses the clinical relevance of NK cells in both primary immunodeficiency and immunotherapy. It is intended to provide an up-to-date and comprehensive overview of this important and interesting innate immune effector cell subset.