Natural killer (NK) cells play a vital role in innate immune responses to infection; they express activation receptors that recognize virus-infected cells. Highly related to receptors recognizing tumor cells, the activation receptors trigger cytotoxicity and cytokine production. NK cells also express inhibitory receptors for major histocompatibility complex (MHC) class I molecules that block the action of the activation receptors. Although many ligands for NK cell receptors have MHC class I folds, recent studies also indicate ligands resembling the NK cell receptors themselves. A combination of immunologic, genetic, biophysical, and in vivo approaches is being employed to understand fully how these receptors contribute to NK cell activities in innate immunity to pathogens and tumors.