Spasticity develops as a result of central nervous system (CNS) injury; however, secondary changes within the muscles and connective tissue also contribute to muscle stiffness. The hyaluronan hypothesis postulates that the accumulation of hyaluronan promotes the development of muscle stiffness. Intramuscular injections of the enzyme hyaluronidase, which hydrolyzes long-chained hyaluronan polymers to smaller polymers, was shown to reduce muscle stiffness and increase passive and active range of motion in patients with spasticity. These results provide preliminary evidence of the hyaluronan hypothesis and suggest an emerging therapy to reduce muscle stiffness using the enzyme hyaluronidase.