Taranabant is a highly selective and potent cannabinoid CB1 receptor inverse agonist. We compared the pharmacological properties of taranabant with another inverse agonist, rimonabant, and determined the preclinical safety margins of taranabant. In vitro studies demonstrated that taranabant is ∼10-fold more potent than rimonabant at the CB1 receptor, and taranabant is more selective based on off-target in vitro screening. In vivo efficacy studies demonstrated that taranabant is ∼10-fold more potent than rimonabant in diet-induced obese rats. In repeat-dose toxicological studies, taranabant did not cause mortality in rodents and monkeys at exposure margins ≤6478 and 1922 times the estimated human exposure at 0.5 mg/day−1. Taranabant did not produce CNS signs, including seizures, when administered to monkeys for 1 year at 10 mg/kg−1day−1 (highest dose tested chronically), corresponding to an exposure margin of 974 times. In contrast to primates, taranabant produced brief handling-induced seizure-like activity in rodents, species predisposed to handling-induced seizures. Throughout the entire preclinical program, taranabant did not cause histopathological changes in the peripheral or central nervous system. In summary, the highly selective nature of taranabant is consistent with its generally favorable preclinical safety profile. Drug Dev Res 2009. © 2009 Wiley-Liss, Inc.