Natural killer (NK) cells are CD56+CD3- large granular lymphocytes that constitute a key component of the human innate immune response. In addition to their potent cytolytic activity, NK cells elaborate a host of immunoregulatory cytokines and chemokines that play a crucial role in pathogen clearance. Furthermore, interactions between NK and other immune cells are implicated in triggering the adaptive, or antigen-specific, immune response. Interleukin-2 (IL-2) and IL-15 are two distinct cytokines with partially overlapping properties that are implicated in the development, homeostasis, and function of NK cells. This review examines the pervasive effects of IL-2 and IL-15 on NK cell biology, with an emphasis on recent discoveries and lingering challenges in the field.