In this review, we develop a blueprint for exercise biology research in the new millennium. The first part of our plan provides statistics to support the contention that there has been an epidemic emergence of modern chronic diseases in the latter part of the 20th century. The health care costs of these conditions were almost two-thirds of a trillion dollars and affected 90 million Americans in 1990. We estimate that these costs are now approaching $1 trillion and stand to further dramatically increase as the baby boom generation ages. We discuss the reaction of the biomedical establishment to this epidemic, which has primarily been to apply modern technologies to stabilize overt clinical problems (e.g., secondary and tertiary prevention). Because this approach has been largely unsuccessful in reversing the epidemic, we argue that more emphasis must be placed on novel approaches such as primary prevention, which requires attacking the environmental roots of these conditions. In this respect, a strong association exists between the increase in physical inactivity and the emergence of modern chronic diseases in 20th century industrialized societies. Approximately 250,000 deaths per year in the United States are premature due to physical inactivity. Epidemiological data have established that physical inactivity increases the incidence of at least 17 unhealthy conditions, almost all of which are chronic diseases or considered risk factors for chronic diseases. Therefore, as part of this review, we present the concept that the human genome evolved within an environment of high physical activity. Accordingly, we propose that exercise biologists do not study "the effect of physical activity" but in reality study the effect of reintroducing exercise into an unhealthy sedentary population that is genetically programmed to expect physical activity. On the basis of healthy gene function, exercise research should thus be viewed from a nontraditional perspective in that the "control" group should actually be taken from a physically active population and not from a sedentary population with its predisposition to modern chronic diseases. We provide exciting examples of exercise biology research that is elucidating the underlying mechanisms by which physical inactivity may predispose individuals to chronic disease conditions, such as mechanisms contributing to insulin resistance and decreased skeletal muscle lipoprotein lipase activity. Some findings have been surprising and remarkable in that novel signaling mechanisms have been discovered that vary with the type and level of physical activity/inactivity at multiple levels of gene expression. Because this area of research is underfunded despite its high impact, the final part of our blueprint for the next millennium calls for the National Institutes of Health (NIH) to establish a major initiative devoted to the study of the biology of the primary prevention of modern chronic diseases. We justify this in several ways, including the following estimate: if the percentage of all US morbidity and mortality statistics attributed to the combination of physical inactivity and inappropriate diet were applied as a percentage of the NIH's total operating budget, the resulting funds would equal the budgets of two full institutes at the NIH! Furthermore, the fiscal support of studies elucidating the scientific foundation(s) targeted by primary prevention strategies in other public health efforts has resulted in an increased efficacy of the overall prevention effort. We estimate that physical inactivity impacts 80-90% of the 24 integrated review group (IRG) topics proposed by the NIH's Panel on Scientific Boundaries for Review, which is currently directing a major restructuring of the NIH's scientific funding system. Unfortunately, the primary prevention of chronic disease and the investigation of physical activity/inactivity and/or exercise are not mentioned in the almost 200 total subtopics comprising t