Based upon ideas about evolution, we put forth the argument that the capacity to transfer energy via aerobic metabolism is such a central feature of mammalian biology, that it must also be the primary determinant of complex disease. From this, we hypothesized that artificial selection on low and high capacity for aerobic exercise would create lines that can be used to define the divide between health and disease. In 1996 we began large-scale divergent selection for aerobic treadmill running capacity in a widely heterogeneous stock of rats (N:NIH). By ten generations we developed lines of low capacity runners (LCR) and high capacity runners (HCR) that on average differed by 317%. As a correlated trait, body mass increased at each generation in the LCR while the body mass decreased in the HCR. The lines also separated for key factors of systemic oxygen transport capacity such as maximal oxygen consumption (VO(2)max), tissue perfusion, capillary density, and oxidative enzyme activity (citrate synthase and B-HAD). We also tested our hypothesis that differences in aerobic energy transfer would produce rats that contrast for risk factors associated with complex disease. Indeed, the lines separated for cardiovascular risk factors including differences in blood pressure, cardiac contractility, visceral adiposity, plasma free fatty acids, and triglycerides. The decrease in aerobic capacity was also associated with low amounts of several proteins required for mitochondrial function.