The increased prevalence of obesity and its co-morbidities and their strong association with inactivity have produced an 'exercise-deficient phenotype' in which individuals with a particular combination of disease-susceptible genes collide with environmental influences to cross a biological 'threshold' that ultimately manifests as overt clinical conditions (i.e., risk-factors for disease states). These risk-factors have been linked to impairments in skeletal muscle mitochondrial function. The question of whether 'inborn' mitochondrial deficiencies and/or defective mitochondrial metabolism contribute to metabolic disease, or if environmental factors are the major determinant, will be examined. We contend that impaired whole-body insulin resistance along with impaired skeletal muscle handling of carbohydrate and lipid fuels (i.e., metabolic inflexibility) is associated with a reduced skeletal muscle mitochondrial content which, in large part, is a maladaptive response to an 'inactivity cycle' which predisposes to a reduced level of habitual physical activity. While genetic components play a role in the pathogenesis of metabolic disease, exercise is a powerful environmental stimulus capable of restoring the metabolic flexibility of fuel selection and reduces risk-factors for metabolic disease in genetically-susceptible individuals.>Given the apathy towards voluntary physical activity in most Western societies, it is clear that there is an urgent need for innovative, clinically-effective exercise strategies, coupled with changes in current attitudes and methods of delivering exercise prescription and dietary advice, in order to improve metabolic health and reduce metabolic disease risk at the population level. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.