This article provides a review of the available scientific evidence related to the structure and function of descending pain inhibitory systems projecting from the periaqueductal gray region to the spinal cord. The importance of these systems in the phenomenon of endogenous analgesia is discussed. The theory that the initial pain-relieving effect of manual therapy procedures may involve activation of these control systems is proposed and a series of hypotheses based on this theoretical concept are presented. Recent studies evaluating the effects of spinal mobilisation procedures are outlined and the outcomes of these studies are discussed in relation to theoretical role of descending pain inhibitory systems in manipulation-induced analgesia. Directions for further research in this area are considered.