Currently our society is faced with the challenge of understanding the biological basis for the epidemics of obesity and many chronic diseases, including Type 2 diabetes. Physical inactivity increases the relative risk of coronary artery disease by 45%, stroke by 60%, hypertension by 30%, and osteoporosis by 59%. Moreover, physical inactivity is cited as an actual cause of chronic disease by the US Centers of Disease Control. Physical activity was obligatory for survival for the Homo genus for hundreds of thousands of years. This review will present evidence that suggests that metabolic pathways selected during the evolution of the human genome are inevitably linked to physical activity. Furthermore, as with many other environmental interactions, cycles of physical activity and inactivity interact with genes resulting in a functional outcome appropriate for the environment. However, as humans are less physically active, there is a maladaptive response that leads to metabolic dysfunction and many chronic diseases. How and why these interactions occur are fundamental questions in biology. Finally, a perspective to future research in physical inactivity-gene interaction is presented. This information is necessary to provide the molecular evidence required to further promote the primary prevention of chronic diseases through physical activity, identify those molecules that will allow early disease detection, and provide society with the molecular information needed to counter the current strategy of adding physical inactivity into our lives.