Myofascial pain syndrome (MPS) is described as the muscle, sensory, motor, and autonomic nervous system symptoms caused by stimulation of myofascial trigger points (MTP), but the participation of fascia in this syndrome has often been neglected. This presentation will explore the important contribution of structural and functional alterations of the deep fascia to the pathophysiology and clinical manifestation of MPS. The interaction of the three dimensional fascial system, with the dynamic nature of sensitization, will be presented in the context of the pathophysiology of MTP and the expression of quantitative, reproducible physical findings in the clinical manifestation of chronic myofascial pain. Emphasis will be given to recent developments in the biology of fascia, and in particular, its hyaluronan (HA)-rich matrix content that provide a viscoelastic property possible cause of MPS. The presentation will translate these findings to highlight novel clinical directions in the diagnosis and non-pharmaceutical management of MPS.