ABSTRACT Support is requested for a Keystone Symposia conference entitled Signals and Mechanisms Underlying the Benefits of Exercise, organized by Drs. Jeffrey Horowitz, Laurie Goodyear and Karyn Esser. The conference will be held in Santa Fe, New Mexico from January 14-17, 2023. A physically active lifestyle is known to be a key component for sustained overall health and well-being; exercise is also used often as a first-line approach for the treatment and/or prevention of many chronic diseases. Despite the overwhelming evidence supporting the health benefits of exercise, the molecular, cellular, tissue, and systemic responses to exercise that underlie these beneficial health effects remain unclear. Deepening our understanding about the mechanistic connections between exercise and health is critical for optimizing lifestyle programs to improve human health across an individual’s lifespan. This Keystone Symposia conference will present new findings addressing the impact of circadian rhythms, sleep, and epigenetics, as well as sex-specific differences on the adaptive responses to exercise. Sessions at this conference will also address the effects of exercise on inflammation, brain function/cognition, and crosstalk between different tissues. The overall goal of this conference is to provide a forum for scientists to discuss the complex responses to exercise, thereby advancing our knowledge about the many health benefits of exercise. In addition, this conference will provide an environment to foster connections and potential future collaborations for the attendees.