The worldwide prevalence of chronic kidney disease (CKD) is high and growing, making CKD a leading cause of mortality. Skeletal muscle wasting, sometimes called sarcopenia or protein-energy wasting, is a frequent, serious consequence of CKD that reduces muscle strength and function, diminishes the quality of life of patients, and raises their risk of comorbidities and death. Muscle atrophy results from a disturbance in muscle protein balance that results from some combination of an increased rate of protein degradation, a decreased rate of protein synthesis, and dysfunctional muscle regeneration. Development of therapeutic strategies to ameliorate muscle loss, or maintain muscle mass, is challenging because of the multifactorial nature of the signals that alter protein homeostasis. This review discusses the cellular signals and mechanisms that negatively alter protein turnover in skeletal muscle during CKD.