The health benefits of regular physical activity are clear, providing a seemingly simple approach to improving public health. Evidence for the benefits of exercise for the prevention of age-related diseases, including cancer, has been accumulating for quite some time and the question of whether exercise is beneficial has largely been answered. There are current public health guidelines calling for adults to engage in at least 150 minutes of moderate-intensity aerobic activity per week to reach the minimum target of exercise that is linked to reduced risk of chronic disease.1 However, there is less evidence to draw from that might support extending the recommendations to include an upper range of exercise that could optimize public health outcomes. Establishing the dose-response relationship of exercise is just like that for pharmacologic therapy—we need to know the minimum effective dose, whether there is a dose-response relationship, and when the point of diminishing returns might be reached. This first question is what led to current public health guidelines for exercise. Rigorously designed and executed dose-response exercise trials will help us answer the next two.