The cannabinoid CB1 receptor belongs to Class A of the G-protein-coupled receptor (GPCR) family. The high constitutive activity of CB1 facilitates inverse agonism at this receptor, and CB1 inverse agonists/antagonists have recently been considered for the treatment of obesity and metabolic syndrome. GPCRs are assumed to have a common topology and to share a common molecular activation mechanism involving their intracellular domains. However, each individual receptor will also have a molecular switch within the ligand binding pocket that is a noncovalent intramolecular interaction in the basal state of the GPCR that must be disrupted to achieve an active state or stabilized to maintain the inactive state. Knowledge of the molecular switch within the ligand binding pocket can greatly facilitate the rational design of inverse agonists and neutral antagonists. This review begins with a brief review on the CB1 receptor and its ligands. The review then focuses on the experimental literature on GPCR structure and activation in Class A receptors. The identification of the molecular switch region in the ligand binding pocket of CB1 (F3.36/W6.48) is discussed and the combined mutation and modeling studies that have led to the identification of interactions key to the inverse agonism of SR141716A are presented. Finally, the development of the first CB1 neutral antagonists based on these modeling/mutation results is discussed. Drug Dev Res 70:585–600, 2009. © 2009 Wiley-Liss, Inc.