Musculoskeletal rehabilitation is based on therapeutic education, exercises and manual therapy. Although many biomechanical models have been proposed, soft tissue and articular manual therapy techniques have not shown they are able to produce significant structural modifications at the level of peripheral tissues. In the last few years, several studies have investigated the mechanisms of manual therapy, identifying neurophysiological peripheral, spinal and supraspinal mechanisms. This article aims to discuss the published literature on this topic, and the potential clinical consequences.