Impaired phosphorylation of adenosine diphosphate represents the fundamental lesion in disorders of muscle energy metabolism. The result is a deficient rate of adenosine triphosphate synthesis relative to utilization, with accumulation of fatigue-promoting hydrolysis products of adenosine triphosphate and related metabolites in circumstances in which the affected pathway normally provides an important contribution to energy production. Increased degradation of muscle adenine nucleotides may accompany this imbalance between muscle energy supply and demand, leading to increased serum uric acid, sometimes associated with gout. Additional factors that may contribute to the pathophysiology of these disorders include depletion of crucial metabolites or cofactors secondary to the enzymatic block; accumulation of toxic metabolites proximal to the block; and dysregulation of preserved metabolic pathways due to altered cellular patterns of regulatory metabolites. Similarly, altered levels of metabolites that normally signal muscle energy demand may alter the regulation of oxygen delivery, ventilation, and neuroendocrine responses to exercise. Finally, the expression of the metabolic defect in other tissues (e.g., central nervous system [CNS], heart, liver) may complicate metabolic myopathies and influences treatment strategies.