Recent advances in the pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFPEF) suggest that noncardiac peripheral factors contribute to the reduced peak Vo₂ (peak exercise oxygen uptake) and to its improvement after endurance exercise training. A greater understanding of the peripheral skeletal muscle vascular adaptations that occur with physical conditioning may allow for tailored exercise rehabilitation programs. The identification of specific mechanisms that improve whole body and peripheral skeletal muscle oxygen uptake could establish potential therapeutic targets for medical therapies and a means to follow therapeutic response.