The mechanisms through which manual therapy inhibits musculoskeletal pain are likely multifaceted and related to the interaction between the intervention, the patient, the practitioner, and the environment. Placebo is traditionally considered an inert intervention; however, the pain research literature suggests that placebo is an active hypoalgesic agent. Placebo response likely plays a role in all interventions for pain and we suggest that the same is true for the treatment effects associated with manual therapy. The magnitude of a placebo response may be influenced by negative mood, expectation, and conditioning. We suggest that manual therapists conceptualize placebo not only as a comparative intervention, but also as a potential active mechanism to partially account for treatment effects associated with manual therapy. We are not suggesting manual therapists include known sham or ineffective interventions in their clinical practice, but take steps to maximize placebo responses to reduce pain.