Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB₁ cannabinoid receptor. In contrast, the CB₂ cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB₂-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB₁-mediated psychoactive effects. CB₂ receptor expression in brain has been partially examined in differentiated cells, while its presence and function in neural progenitor cells remain unknown. Here we show that the CB₂ receptor is expressed, both in vitro and in vivo, in neural progenitors from late embryonic stages to adult brain. Selective pharmacological activation of the CB₂ receptor in vitro promotes neural progenitor cell proliferation and neurosphere generation, an action that is impaired in CB₂-deficient cells. Accordingly, in vivo experiments evidence that hippocampal progenitor proliferation is increased by administration of the CB₂-selective agonist HU-308. Moreover, impaired progenitor proliferation was observed in CB₂-deficient mice both in normal conditions and on kainate-induced excitotoxicity. These findings provide a novel physiological role for the CB₂ cannabinoid receptor and open a novel therapeutic avenue for manipulating neural progenitor cell fate.--Palazuelos, J., Aguado, T., Egia, A., Mechoulam, R., Guzmán, M., Galve-Roperh, I. Non-psychoactive CB₂ cannabinoid agonists stimulate neural progenitor proliferation.