Skeletal muscle breakdown occurs normally with exercise, followed by muscle repair and physiologic adaptation. Strenuous, unaccustomed, prolonged, and repetitive exercise, particularly when associated with other risk factors such as hot and humid climate or sickle cell trait can cause clinically significant exertional rhabdomyolysis (ER). Although most cases are asymptomatic and resolve without sequelae, ER is the most common cause of exercise-related myoglobinuric acute renal injury and acute renal failure in athletes. Exercise-related muscle pain, elevated serum creatine kinase (CK), and "cola-colored" urine have been described as a classic presentation of ER. The exact mechanism of ER has not been clearly elucidated. Most studies suggest a cascade of events that include depletion of adenosine triphosphate (ATP), impaired function of the Na+- K+ ATPase system, intracellular excess calcium accumulation, sarcolemma damage, and release of intracellular proteins and other substances into blood. Excess myoglobin that is filtered at the glomerulus can lead to myoglobinuric acute renal injury. Cessation of physical activity, relative rest during clinical recovery, and early aggressive fluid replacement are mainstays of treatment. Return to play after recovery from ER is influenced by associated risk factors that may predispose the athlete to recurrence and is guided by signs, symptoms, and CK levels. This article reviews the definitions, pathophysiology, diagnosis, and management of ER with specific relevance to acute kidney injury.