The daily turnover of cellular proteins is large, with amounts equivalent to the protein contained in 1.0 to 1.5 kg of muscle. Consequently, even a small, persistent increase in the rate of protein degradation or decrease in protein synthesis will result in substantial loss of muscle mass. Activation of protein degradation in the ubiquitin-proteasome system is the mechanism contributing to loss of muscle mass in kidney disease. Because other catabolic conditions also stimulate this system to cause loss of muscle mass, the identification of activating signals is of interest. A complication of kidney disease, metabolic acidosis, activates this system in muscle by a process that requires glucocorticoids. The influence of inflammatory cytokines on this system in muscle is more complicated, as evidence indicates that cytokines suppress the system, but glucocorticoids block the effect of cytokines to slow protein breakdown in the system. New information identifying mechanisms that activate protein breakdown and the rebuilding of muscle fibers would lead to therapies that successfully prevent the loss of muscle mass in kidney disease and other catabolic illnesses.