Sex differences in substrate metabolism during moderate-intensity endurance exercise have been well established. Specifically, at the whole body level women have a lower respiratory exchange ratio (RER) during moderate-intensity endurance exercise as compared with men (1), indicative of a lesser reliance on whole body carbohydrate (CHO) oxidation to support exercise fuel needs. In fact, as compared with men, women have a lower reliance on both liver [decreased glucose rate of appearance (Ra), rate of disappearance (Rd) and metabolic clearance rate (MCR)] and muscle glycogen stores during moderate-intensity endurance exercise (1). Furthermore, while the effects of sex on intramyocellular lipid (IMCL) utilization during endurance exercise are controversial, women have a greater depot of IMCL available to support exercise fuel needs and a greater percentage of IMCL in contact with mitochondria following a bout of moderate-intensity endurance exercise as compared with men (2), suggestive of a greater capacity to utilize IMCL. These sex differences in metabolism during endurance exercise are known to be mediated by estrogen. Indeed, estrogen supplementation to young men decreases RER and liver glycogen utilization, with no effect on muscle glycogen utilization during moderate-intensity endurance exercise (3, 4). However, while not impacting muscle glycogen utilization, estrogen supplementation did lower muscle glycogen stores prior to exercise (3), which may precede changes in muscle glycogen utilization should estrogen supplementation continue, as is seen when comparing men to women. Given that estrogen concentrations fluctuate across the menstrual cycle it is not surprising that substrate metabolism during moderate-intensity endurance exercise also varies across the menstrual cycle. In the luteal phase when estrogen levels are high, women have a lower liver and muscle glycogen utilization as compared with women in the follicular phase (1). Taken together, these findings support substantial differences in muscle metabolism during moderate-intensity endurance exercise between men and women and within women across the menstrual cycle, which may impact the response to exercise and nutritional strategies aimed at improving health and performance in women. Despite these well-recognized differences in substrate metabolism during endurance exercise between men and women and across the menstrual cycle, there is a paucity of research examining the effects of exercise and nutritional regimes aimed to enhance performance and/or health in women. Furthermore, the evidence that does exist is suggestive of discordance in the effectiveness of nutritional and exercise regimes between the sexes. While we have reached the era of personalized sport nutrition, we are without a sufficient body of evidence to truly optimize sport nutrition in women athletes. It is not just sport performance where the benefits of exercise and nutrition in women are unknown, the effects of specific exercise and nutritional regimes to optimize health in women are also not completely understood. The focus of this talk will be to provide an overview of the well-established sex differences in metabolism during endurance exercise and how they relate to the existing data showing sex differences in response to nutritional (i.e. carbohydrate loading, creatine, protein) and exercise strategies (i.e. high intensity interval training, resistance exercise) intended to improve exercise performance and/or health.