The metabolic configurations employed by immune cells are critical for supporting their cell-specific immune responses. Natural killer (NK) cells are able to act quickly to exert their effector functions and have an established metabolic configuration to support these immediate innate actions. When acting over longer periods, NK cells can undergo dynamic changes in numerous metabolic pathways to fuel and regulate prolonged NK cell responses. In this chapter, we describe the current understanding of what fuels NK cells, and the metabolic pathways that convert these fuels into the energy and biomaterials required for effective responses during infection and cancer. The regulation of NK cell metabolism from intrinsic and extrinsic signals is discussed, in addition to mechanisms leading to impaired NK cell metabolism and function in pathologies such as cancer.