Manual therapy (MT) is a passive, skilled movement applied by clinicians that directly or indirectly targets a variety of anatomical structures or systems, which is utilized with the intent to create beneficial changes in some aspect of the patient pain experience. Collectively, the process of MT is grounded on clinical reasoning to enhance patient management for musculoskeletal pain by influencing factors from a multidimensional perspective that have potential to positively impact clinical outcomes. The influence of biomechanical, neurophysiological, psychological and nonspecific patient factors as treatment mediators and/or moderators provides additional information related to the process and potential mechanisms by which MT may be effective. As healthcare delivery advances toward personalized approaches there is a crucial need to advance our understanding of the underlying mechanisms associated with MT effectiveness.