Agonist‐induced internalization of G protein‐coupled receptors (GPCRs) is an important mechanism for regulating signaling transduction of functional receptors at the plasma membrane. We demonstrate here that both caveolae/lipid‐rafts‐ and clathrin‐coated‐pits‐mediated pathways were involved in agonist‐induced endocytosis of the cannabinoid type 1 receptor (CB1R) in stably transfected human embryonic kidney (HEK) 293 cells and that the internalized receptors were predominantly sorted into recycling pathway for reactivation. The treatment of CB1 receptors with the low endocytotic agonist Δ9‐THC induced a faster receptor desensitization and slower resensitization than the high endocytotic agonist WIN 55,212‐2. In addition, the blockade of receptor endocytosis or recycling pathway markedly enhanced agonist‐induced CB1 receptor desensitization. Furthermore, co‐expression of phospholipase D2, an enhancer of receptor endocytosis, reduced CB1 receptor desensitization, whereas co‐expression of a phospholipase D2 negative mutant significantly increased the desensitization after WIN 55,212‐2 treatment. These findings provide evidences for the importance of receptor endocytosis in counteracting CB1 receptor desensitization by facilitating receptor reactivation. Moreover, in primary cultured neurons, the low endocytotic agonist Δ9‐THC or anandamide exhibited a greater desensitization of endogenous CB1 receptors than the high endocytotic agonist WIN 55,212‐2, CP 55940 or 2‐arachidonoyl glycerol, indicating that cannabinoids with high endocytotic efficacy might cause reduced development of cannabinoid tolerance to some kind cannabinoid‐mediated effects.