Natural killer (NK) cells mediate innate defense against viral infections, but the mechanisms in place to access their functions as needed during diverse challenges while limiting collateral damage are poorly understood. Recent molecular characterization of effects mediated through infection-induced inhibitory/activating NK receptor-ligand pairs and cytokines are providing new insights into pathways regulating their responses and revealing unexpected consequences for NK cell subset effects, maintenance, proliferation and function through times overlapping with adaptive and long-lived immunity. The observations define flexible pathways for experience-induced 'conditioning' and challenge narrowly defined roles for NK cells and innate immunity as first responders with prescribed functions. They suggest that individual experiences as well as genes influence the innate immune resources available to fight off an infection.