The origin of symptom of exercise intolerance is still considered one of the major challenges among scientists and clinicians involved in the care of patients with chronic heart failure (CHF). In contrast to the traditional vision that saw a malfunction of the heart as a pump as the leading cause, in the last 20 years there has been mounting evidence that the complex pathophysiology of CHF begins with an abnormality of the heart as a “primum movens”, but involves adaptive changes in many body parts, including the cardiovascular, musculoskeletal, renal, neuroendocrine, haemostatic, immune, and inflammatory systems. These systems’ changes are playing key roles in the HF expression and progression. Alterations in skeletal muscle mass are also of importance in limiting peak functional capacity in patients with CHF, as reduced physical activity (disuse and immobilisation in advanced stages) plays some part in the muscle alterations in CHF. On the whole, these abnormalities resemble those induced by physical deconditioning. A great bulk of evidence, originally from our Lab., has pointed towards the existence of a reflex network that becomes hyperactive secondary to skeletal muscle alterations due to peripheral modification including early occurrence of acidosis, early depletion of high energetic metabolic factors, particularly in the skeletal muscle. The overactivation of signals originating from skeletal muscle receptors (mechano-metaboreceptors) is an intriguing hypothesis proposed to explain the origin of symptoms and the beneficial effect of exercise training in the CHF syndrome. These reflexes may contribute to sympathetic overactivation, to exercise intolerance, and to the progression of CHF syndrome. The so called metaboreflex has been demonstrated to be hyperactive in CHF and to be responsible for paradoxical increase in systemic vascular resistance and decrease in cardiac output whenever activated in these patients. Recently, it was found in heart transplant recipients that, after transplant, despite improved cardiac function, re-setting of metaboreflex-induced cardiovascular adjustments to exercise requires months in these patients, thereby suggesting that this reflex was dys-regulated before transplant.