Complex regional pain syndrome (CRPS) is the result of changes to the somatosensory systems that process noxious, tactile, and thermal information; to the sympathetic systems that innervate skin (blood vessels, sweat glands); and to the somatomotor systems. The changes suggest that the CNS representations of the systems have been altered. Patients with CRPS also have peripheral changes (eg, oedema, signs of inflammation, sympathetic-afferent coupling [the basis for sympathetically maintained pain], and trophic changes) that cannot be explained by central changes. On the basis of clinical observation and research in human beings and animals, we hypothesise that CRPS is a systemic disease involving the CNS and peripheral nervous system. The most important question for future research is what causes CRPS? In this article, we suggest a change to the focus of research efforts and treatment. We also suggest there be diagnostic reclassification and redefinition of CRPS.