Chronic heart failure (CHF) patients are characterized by a reduction in functional capacity, which appears to have only a weak relation with central hemodynamic parameters. Recent studies suggest that changes in the periphery, like those occurring in the skeletal muscles of patients with CHF, might play an important role in the origin of symptoms and exercise intolerance in this condition. It has been shown that biochemical and histological changes in the skeletal muscles of CHF patients relate with the degree of exercise intolerance, as expressed by peak oxygen consumption (pVO2) better than resting hemodynamic parameters. A reduction in skeletal muscle mass represents another important determinant of exercise intolerance in CHF patients. In a recent study, in fact, it has been shown that the total skeletal muscle mass, as assessed by total body X-ray absorptiometry, is a significant predictor of pVO2 in a population of ambulatory CHF patients independently of NYHA functional class and neurohormonal activation. The relation between skeletal muscle mass and pVO2 might also contribute to explain the differences in exercise capacity observed between men and women. This relation is not surprising, as oxygen uptake during exercise occurs in the metabolically active tissues, i.e. the skeletal muscles. For the same reason, the correction of pVO2 for skeletal muscle mass instead of total body weight would represent a more physiological approach. This correction might also contribute to improve the prognostic power of pVO2 in those groups of patients, like women and obese patients, in whom it is still not clear. Finally, the relationship between skeletal muscle changes and exercise intolerance suggests the possibility to modify the peripheral changes in order to improve functional capacity in CHF patients. Recent studies have shown that the administration of ACE-inhibitors and angiotensin II receptor blockers can improve the properties of the skeletal muscles in animal and human models. Another important tool to improve exercise capacity in CHF patients is represented by rehabilitation. Exercise training, in fact, allows to obtain an improvement in pVO2, which parallels important biochemical and histological changes in the skeletal muscles.