There is intense scientific, medical, and societal interest in the endocannabinoid system (ECS) because it modulates a wide range of brain functions including mood, appetite/energy expenditure, and learning and memory. However, because of the complex and pleotropic pharmacology of the ECS, cannabinoid drugs are associated with unwanted neurological and psychoactive side effects. These limitations drive the need for increased biochemical and cell biological understanding of the ECS and a reappraisal of how this system may be targeted therapeutically.Endocannabinoid signalling mediated by cannabinoid type 1 receptors (CB1Rs) is critical for homeostatic neuromodulation of both excitatory and inhibitory synapses. This requires highly polarised axonal surface expression of CB1R, but how this is achieved remains unclear. We previously reported that the H9 domain in the intracellular C-terminus of CB1R contributes to polarised surface expression by an unknown mechanism. Here we show the H9 domain binds to the endocytic adaptor protein SGIP1 to promote CB1R expression in the axonal membrane. Overexpression of SGIP1 increases CB1R axonal surface localisation but has no effect on CB1R lacking the H9 domain (CB1RΔH9). Conversely, SGIP1 knockdown, as well as overexpression of an H9 peptide alone, reduces axonal surface expression of CB1R. Furthermore, SGIP1 knockdown diminishes CB1R-mediated inhibition of presynaptic Ca2+ influx in response to neuronal activity. Together, these data advance mechanistic understanding of endocannabinoid signalling by demonstrating that SGIP1 interaction with H9 underpins axonal CB1R surface expression to regulate presynaptic responsiveness and suggest that manipulating this interaction could be used for potential therapeutic benefit.