It is a fact that a large proportion of HF R428 patients would trade increased length of life for increased quality of life, which in HF patients is directly linked to exercise capacity. Surprisingly, exercise dysfunction in HF patients is not directly related to severity of left ventricular dysfunction, intra-cardiac hemodynamics at rest or during exercise, or inadequate skeletal muscle blood flow. Instead, exercise dysfunction is directly related to abnormalities of the skeletal muscles themselves; in fact a skeletal myopathy has been described which includes a fiber shift from type I aerobic fibers to type II anaerobic fibers and decreased mitochondrial volume and metabolic function. Skeletal muscle function depends critically on both intact energy metabolism and on the robustness of the sequence of events linking the electrical with the mechanical activation of the muscle fibers. The role of metabolic deficiencies in skeletal muscle function in HF patients on optimal medical therapy has recently been questioned. We have recently reported marked abnormalities of several key proteins participating in the ECC process in humans with HF. Tacrolimus is the backbone of immunosuppressive drug used worldwide in organ transplantation and characterized by a narrow therapeutic range and high inter-individual variability in its pharmacokinetics. To achieve the desired target blood concentrations is of critical importance to avoid rejection and dose-related adverse effects after transplantation. The variability makes it difficult to establish an empirical dose regimen for this drug, especially in pediatric patients, in whom 100-fold variability in pharmacokinetic parameters and blood concentration after a fixed dose is routinely observed. Underexposure to TAC may result in immunosuppression failure and acute rejection in recipients. On the other hand, overexposure to it may put patients at risk for its considerable toxicity. Therefore, maintaining the drug exposure within this narrow safe therapeutic window becomes a critical aspect in patient management. Concerning the concept that young children need a higher TAC dose than adult patients, the blood TAC concentration should be monitored regularly to maintain a therapeutic range, when the risk of rejection is the highest. Although various factors, such as age, sex, body weight, drug interactions and other factors lead to the wide range of interpatient variability ineffective dosage of TAC, among them genetic factors play a critical role in the pharmacokinetic properties and therapeutic levels of TAC. Therapeutic drug monitoring of TAC in blood is necessary to provide an effective immunosuppression and avoid adverse effects after organ transplantation.