Obesity is known to be associated with variety of complex diseases including hypertension, cardiovascular disease, diabetes, affective disorders, and some cancers. The heterogeneous genetic (G) and environmental (E) conditions of human populations impart considerable difficulty for uncovering a common etiology between complex disease and their associated risk factors. Development of animal models where G and E variation are more controlled can provide a useful path for both mechanistic exploration and validation of human data. In 1996, we began development of what we thought would be more meaningful models for the study of complex disease. Based upon ideas on evolution of biologic complexity, we propose that aerobic capacity is mechanistically linked to features that divide between health and disease. If true, we hypothesized that artificial selective breeding for low and high aerobic exercise capacity in rats would yield animal models that contrast in propensity for development of complex disease. Here we review basic properties of a model organism to suggest that these rat models represent a more ideal substrate for mechanistic exploration of the GxE interaction between aerobic capacity and risk for complex disease.