Obesity is extremely prevalent in the U.S., associated with numerous chronic diseases and an economic burden on the health care system. Exercise results in beneficial health outcomes, protects against a variety of chronic diseases and can reduce body mass and fat. U.S. exercise guidelines recommend identical exercise programs for everyone regardless of age, sex or genetic background. Furthermore, individual variation in responses to recommend exercise programs occurs across a variety of responses with some individuals experiencing adverse responses, including fat gain. In order to establish effective exercise guidelines, dissection of underlying physiological mechanisms and driving factors as well as the evaluation of potential interventions needs to occur. Experimental mouse models of exercise-induced adverse outcomes will be valuable in identification of mechanisms and evaluation of interventions while overcoming limitations in human studies. Several studies have identified individual mice exhibiting adverse fat gain following exercise, but no systematic effort has been conducted to identify and characterize models of adverse response. Strains from the Collaborative Cross (CC) genetic reference population were used due to its high levels of genetic variation, its reproducible nature, and the observation that the CC is a rich source of novel disease models, to assess the impact genetic background has on exercise responses. This thesis work aimed to identify and develop mouse models of exercise-induced adverse body composition response and to determine the effect of different factors, including age, sex, exercise program and genetic background, on body composition response. In an initial study, we assessed body composition responses to voluntary exercise in aged females from 42 CC strains. We observed significant variation in body composition responses due to genetic background. Some strains, in particular CC027/GeniUnc, had an adverse body composition response. An additional study identified CC002/Unc as a model of voluntary exercise-induced adverse body composition response in old females. Unlike the initial screen, this study took advantage of age matched females with a case – control experimental design to account for body composition changes due to aging. Additionally, we measured body composition and metabolic responses to different forced exercise programs (HIIT and MICT) in a subset of four CC strains. We found body composition responses to different exercise programs varied by sex and further by genetic background. Overall, females had more beneficial body composition responses to HIIT than MICT programs. Across these studies we have demonstrated that genetic background has a significant effect on responses to exercise and further genetic background interacts with other factors to influence these responses. Additionally, we evaluated body composition and metabolism responses to long-term exercise during aging in C57BL/6J mice. We observed body mass and composition response trajectories to long-term exercise vary dependent on sex. Overall, exercise was protective against age related changes in body mass and composition. This work provides novel models for studies to determine the mechanisms behind adverse metabolic responses to exercise and enables development of more rational personalized exercise recommendations based on factors such as age, sex, and genetic background.