Rhabdomyolysis is a well-known clinical syndrome of muscle injury associated with myoglobinuria, electrolyte abnormalities, and often acute kidney injury (AKI). The pathophysiology involves injury to the myocyte membrane and/or altered energy production that results in increased intracellular calcium concentrations and initiation of destructive processes. Myoglobin has been identified as the primary muscle constituent contributing to renal damage in rhabdomyolysis. Although rhabdomyolysis was first described with crush injuries and trauma, more common causes in hospitalized patients at present include prescription and over-the-counter medications, alcohol, and illicit drugs. The diagnosis is confirmed by elevated creatine kinase levels, but additional testing is needed to evaluate for potential causes, electrolyte abnormalities, and AKI. Treatment is aimed at discontinuation of further skeletal muscle damage, prevention of acute renal failure, and rapid identification of potentially life-threatening complications. Review of existing published data reveals a lack of high-quality evidence to support many interventions that are often recommended for treating rhabdomyolysis. Early and aggressive fluid resuscitation to restore renal perfusion and increase urine flow is agreed on as the main intervention for preventing and treating AKI. There is little evidence other than from animal studies, retrospective observational studies, and case series to support the routine use of bicarbonate-containing fluids, mannitol, and loop diuretics. Hyperkalemia and compartment syndrome are additional complications of rhabdomyolysis that must be treated effectively. A definite need exists for well-designed prospective studies to determine the optimal management of rhabdomyolysis.