Treatment of ob/ob mice with a Cannabinoid receptor 1 (Cnr1) antagonist reduces food intake suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knock-out ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced insulin-like growth factor 1 levels without alterations of growth hormone levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist which had no effect on glucose metabolism suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also show similar leptin senstivity as ob/ob mice suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data further suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-1 axis and improve β bell function and glucose homeostasis in the setting of leptin deficiency.