The endocannabinoid system (ECS) plays a fundamental role in the regulation of synaptic transmission. Exposure to stressful events triggers synaptic adaptations in many brain areas. The activity of the ECS in stress-responsive neural circuits suggests that it may be involved in the behavioral responses and synaptic effects typical of stress. In this review, we discuss evidence demonstrating that striatal ECS is modulated by stress. Chronic stress exposure alters endocannabinoid levels, cannabinoid CB1 receptor binding and cannabinoid CB1 receptor-mediated control of inhibitory synaptic transmission in the striatum. Recent studies have shown that impairment of endocannabinoid signalling is associated with inability to adapt to chronic stress and to the development of maladaptive behaviors. The ECS represents a novel potential pharmacological target to treat stress-associated neuropsychiatric conditions.