Relatively few studies have compared the effects of tetrahydrocannabinols and anandamide-like cannabinoids following repeated dosing. Whereas pronounced tolerance develops to many of the in vivo pharmacological effects of Delta9-tetrahydrocannabinol with repeated dosing, tolerance to anandamide-induced effects is typically less noted. In the present study, we examined cross-tolerance between Delta9-tetrahydrocannabinol and anandamide-like compounds (anandamide, 2-methylanandamide, and O-1812) in a tetrad of in vivo tests sensitive to cannabinoid action, including spontaneous activity, tail flick, rectal temperature, and a ring immobility test of catalepsy. Six intraperitoneal injections of Delta9-tetrahydrocannabinol 10 mg/kg over a period of 4 days resulted in the development of pronounced tolerance to all of its in vivo effects. In contrast, task specificity was observed in cross-tolerance to anandamide and its analogs: antinociception (all three compounds), suppression of spontaneous activity (2-methylanandamide and O-1812), catalepsy (O-1812), and hypothermia (none of the compounds). Furthermore, when it occurred, the magnitude of cross-tolerance was notably smaller. These results suggest that anandamide-like cannabinoids may have a unique pharmacology that only partially overlaps with that of Delta9-tetrahydrocannabinol and other traditional cannabinoids. Although the basis for this unique pharmacology has not as yet been determined, it is possible that regional specificity of cannabinoid CB1 receptor downregulation and endocannabinoid release induced by repeated dosing with Delta9-tetrahydrocannabinol may play a role.