Vaccination serves as a cornerstone of global health. Successful prevention of infection or disease by vaccines is achieved through elicitation of pathogen-specific antibodies and long-lived memory T cells. However, several microbial threats to human health have proven refractory to past vaccine efforts. These shortcomings have been attributed to either inefficient triggering of memory T and B cell responses or to the unfulfilled need to stimulate non-conventional forms of immunological memory. Natural killer (NK) cells have recently emerged as both key regulators of vaccine-elicited T and B cell responses and as memory cells that contribute to pathogen control. We discuss potential methods to modulate these functions of NK cells to enhance vaccine success.