Patients on dialysis have extremely limited exercise capacity, and poor physical functioning has been linked to low quality of life and high mortality in this population. The reason for the debility of patients on dialysis is far from clear despite years of study. The anemia of chronic renal disease is clearly a contributing factor, but uremic myopathy and resulting decreased muscle oxygen utilization have a significant impact on the physical functioning of patients on dialysis as well. Although it is likely that factors related to uremia adversely affect muscle function, some of the abnormalities demonstrated in uremic muscle are consistent with disuse atrophy. The clear contribution of anemia and the possible role of limited physical activity have led to studies of the effects of erythropoietin and aerobic exercise training on exercise capacity in end-stage renal disease patients. Both of these interventions result in increased exercise capacity. Thus vigorous treatment of anemia and uremia and encouragement of physical activity are important interventions to maximize the physical functioning of patients on dialysis. In addition, more studies are needed to clarify the causes of debility in this population and the impact of interventions on physical functioning, quality of life, and mortality.