Muscle wasting increases the morbidity and mortality associated with chronic kidney disease (CKD) and has been attributed to malnutrition. In most patients, this is an incorrect diagnosis because simply feeding more protein aggravates uremia. Instead, there are complex mechanisms that stimulate loss of skeletal muscle, involving activation of mediators that stimulate the ATP-dependent ubiquitin-proteasome system (UPS). Identified mediators of muscle protein breakdown include inflammation, metabolic acidosis, angiotensin II, and neural and hormonal factors that cause defects in insulin/insulin-like growth factor I (IFG-I) intracellular signaling processes. Abnormalities in insulin/IGF-I signaling activate muscle protein degradation in the UPS and caspase-3, a protease that disrupts the complex structure of muscle proteins to provide substrates for the UPS. During the cleavage of muscle proteins, caspase-3 leaves behind a characteristic 14-kD actin fragment in the insoluble fraction of muscle, and characterization of this fragment identifies the presence of muscle catabolism. Thus, it could become a marker of excessive muscle wasting, providing a method for early detection of muscle wasting. Another consequence of activation of caspase-3 in muscle is stimulation of the activity of the proteasome, which increases the degradation of muscle proteins. Treatment strategies for blocking muscle wasting include correction of metabolic acidosis, which can suppress muscle protein losses in patients with CKD who are or are not being treated by dialysis. Correcting acidosis also improves bone metabolism in CKD and hence should be a goal of therapy. Exercise training is a potentially beneficial approach, but more information is needed to optimize exercise regimens. Replacing testosterone deficits can improve muscle mass in men, but dosing and side effects in women have not been adequately tested. Although insulin resistance occurs early in the course of CKD, there are no effective means of correcting it. Consequently, new therapies that can safely suppress muscle wasting are needed.