Abstract Cannabinoids are well known modulators of mood and emotional behavior. Current research supports a role for endocannabinoid signaling in the treatment of depression. Changes in levels of the cannabinoid CB 1 receptor or the endogenous CB 1 receptor ligands, anandamide and 2-AG, are observed both in humans suffering from depression and in animal models of depression, and experimental manipulation of CB 1 receptor signaling has also been shown to affect emotional reactivity in rodents. Importantly, inhibitors of anandamide inactivation have demonstrated efficacy in enhancing stress-coping and mood-related behavior. This article will review these areas of research, highlighting the potential of endocannabinoid metabolism modulators as therapeutics for the treatment of depression.