The origin of the myofascial trigger point (TrP), an anomalous locus in muscle, has never been well-described. A new trigger point hypothesis (the new hypothesis) presented here addresses this lack. The new hypothesis is based on the concept that existing myoprotective feedback mechanisms that respond to muscle overactivity, low levels of adenosine triphosphate, (ATP) or a low pH, fail to protect muscle in certain circumstances, such as intense muscle activity, resulting in an abnormal accumulation of intracellular Ca2+, persistent actin-myosin cross bridging, and then activation of the nociceptive system, resulting in the formation of a trigger point. The relevant protective feedback mechanisms include pre- and postsynaptic sympathetic nervous system modulation, modulators of acetylcholine release at the neuromuscular junction, and mutations/variants or post-translational functional alterations in either of two ion channelopathies, the ryanodine receptor and the potassium-ATP ion channel, both of which exist in multiple mutation states that up- or downregulate ion channel function. The concepts that are central to the origin of at least some TrPs are the failure of protective feedback mechanisms and/or of certain ion channelopathies that are new concepts in relation to myofascial trigger points.