Patients with chronic renal failure suffer from a muscle wasting syndrome that is characterized by loss of lean body mass and negative nitrogen balance. Evidence is provided indicating that metabolic acidosis plays a major role in initiating these adverse effects. In particular, we discuss findings suggesting that metabolic acidosis mitigates its effects by activating the cytosolic ubiquitin proteasome proteolytic pathway. Additional evidence that metabolic acidosis alters vitamin D and parathyroid hormone levels is provided. Therapy that includes correction of the metabolic acidosis with alkali in the form of sodium bicarbonate supplements has significant therapeutic implications for uremic patients with even mild degrees of metabolic acidosis.