To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tips.2007.10.006 Byline: Ruth A. Ross Abstract: In 2005, the first evidence was obtained that the cannabinoid CB.sub.1 receptor contains an allosteric binding site. The site can be recogni zed by synthetic small molecules, which display a markedly divergent effect on orthosteric ligand affinity versus efficacy; these small molecules are allosteric enhancers of agonist binding affinity and allosteric inhibitors of agonist signalling efficacy. Allosteric modulation heralds a new approach to the manipulation of the endocannabinoid system for therapeutic benefit; it promises to augment the existing portfolio of selective direct agonists, competitive antagonists and enzyme inhibitors. Author Affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK