BACKGROUND AND PURPOSE: Many studies have shown associations between risk of morbidity and mortality with both obesity and low physical activity (PA), but association does not imply causality. Moreover, there is an inverse relationship between PA and obesity; therefore, controlling for one of these factors when investigating the risk associated with the other is essential. The purpose of this review is to determine whether low PA and obesity actually cause metabolic dysfunction and chronic disease, especially type 2 diabetes (T2D), rather than simply operating as predictors or markers. METHODS: The case for causality is strengthened if the following two conditions are satisfied: first, that significant associations between obesity or low PA and risk persist after controlling appropriately; and second, that the physiological mechanisms by which obesity or low PA may exert a causal effect are clearly established. The studies examined include those that have used cardiorespiratory (CR) fitness as a surrogate measure for PA, thus also providing evidence for low CR fitness as an independent risk factor in its own right. RESULTS AND CONCLUSIONS: Low PA and poor CR fitness are independent predictors of mortality related to type 2 diabetes and chronic disease in general. Together with well-demonstrated mechanisms, there is strong evidence that low PA and low CR fitness are direct, independent causes of metabolic dysfunction and type 2 diabetes. Despite some reports to the contrary, there is evidence that both general and visceral obesity are predictors of mortality and morbidity after controlling for PA. However, in the absence of established mechanisms, evidence is insufficient to conclude that either general or visceral obesity is a direct, independent cause of metabolic dysfunction or type 2 diabetes.