Randomized clinical trials of exercise training regimens in sedentary individuals have provided a mechanistic understanding of the long-term health benefits and consequences of physical activity and inactivity. The sedentary control periods from these trials have provided evidence of the progressive metabolic deterioration that results from as little as 4–6 mo of continuing a physically inactive lifestyle. These clinical trials have also demonstrated that only a modest amount of physical activity is required to prevent this metabolic deterioration, and this amount of physical activity is consistent with current physical activity recommendations (150 min/wk of moderate intensity physical activity). These recommendations have been issued to the general population for a vast array of health benefits. While greater adherence to these recommendations should result in substantial improvements in the health of the population, these recommendations still remain inadequate for many individuals. An individual's physical activity requirements are influenced by such factors as an individual's diet, nonexercise physical activity patterns, genetic profile, and medications. Improving the understanding of how these factors influence an individual's physical activity requirements will help advance the field and help move the field toward the development of more personalized physical activity recommendations.