Myofascial pain syndrome is an important health problem. It affects a majority of the general population, impairs mobility, causes pain, and reduces the overall sense of well-being. Underlying this syndrome is the existence of painful taut bands of muscle that contain discrete, hypersensitive foci called myofascial trigger points. In spite of the significant impact on public health, a clear mechanistic understanding of the disorder does not exist. This is likely due to the complex nature of the disorder which involves the integration of cellular signaling, excitation-contraction coupling, neuromuscular inputs, local circulation, and energy metabolism. The difficulties are further exacerbated by the lack of an animal model for myofascial pain to test mechanistic hypothesis. In this review, current theories for myofascial pain are presented and their relative strengths and weaknesses are discussed. Based on new findings linking mechanoactivation of reactive oxygen species signaling to destabilized calcium signaling, we put forth a novel mechanistic hypothesis for the initiation and maintenance of myofascial trigger points. It is hoped that this lays a new foundation for understanding myofascial pain syndrome and how current therapies work, and gives key insights that will lead to the improvement of therapies for its treatment. 1. Significance Myofascial pain is a significant health problem affecting as much as 85 % of the general population sometime in their lifetime while the estimated overall prevalence is ~46 % [1, 2]. Myofascial pain syndrome is collection of the sensory, motor, and autonomic symptoms that include local and referred pain, decreased range of motion, and weakness. The health impact of myofascial pain can be quite severe as patients with the disorder not only suffer from decreased functional status associated with musculoskeletal pain and loss of function, but also suffer from impaired mood as well as decreased quality of life [3]. While myofascial pain syndrome is complex in its presentation, the onset and persistence of myofascial pain syndrome are known to be caused by myofascial trigger points [4]. In patients, myofascial trigger points present as focal areas in muscle that appear stiff and

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