Treatment mechanisms reflect the underlying processes or pathways through which a treatment or intervention produces its effects on an outcome. For force-based manipulations (which include manual therapies), treatment mechanisms have been measured in multiple animal and preclinical studies. In this commentary, we argue that measuring treatment mechanisms of force-based manipulation is highly complex, most notably because these mechanisms: 1) frequently interact locally and regionally with unmeasured variables; 2) are influenced by time, clinician, environments, and a litany of other mediators; and 3) are likely variable because people respond differently to all interventions. For each challenge, we provide recommendations on how to improve study design methodology and clarity of inference. Lastly, we provide a "Call for Action" to improve manual therapy mechanistic research, because studying the mechanisms of force-based manipulations is critical for advancing both scientific knowledge and clinical practice.