The endocannabinoid system has recently emerged as a promising therapeutic target for the treatment of stress-related emotional disorders. A growing literature base has collectively demonstrated that facilitation of endocannabinoid signaling promotes antidepressant- and anxiolytic-like responses in preclinical animal models, while disruption of this system profoundly affects emotion, cognition, and neuroendocrine functioning. Although these findings are encouraging, the role of endocannabinoid signaling within discrete corticolimbic brain structures is considerably complex. Consequently, researchers have recently shifted focus to examining the effects of local cannabinoid manipulations on emotion from a neuroanatomical standpoint. This review provides an overview of the site-specific effects of cannabinergic compounds in preclinical tests of emotionality, as well as the alterations in endocannabinoid signaling observed in animal models of depression. Broadly speaking, these studies indicate that CB(1) receptors in the medial prefrontal cortex and ventral hippocampus appear to be responsible for the antidepressant- and anxiolytic-like phenotype elicited by systemic CB(1) receptor agonists, which parallels biochemical studies showing that endocannabinoids are downregulated in these two regions following exposure to chronic stress. Conversely, CB(1) receptor activation within distinct amygdalar nuclei yields opposing effects on emotional behavior, such that local stimulation of CB(1) receptors in the basolateral amygdala and central amygdala promoting anxiogenesis and anxiolysis, respectively. Moreover, a series of elegant studies has revealed that cannabinoid transmission in the basolateral amygdala strongly modulates the acquisition and processing of associative fear memory via interactions with the medial prefrontal cortex. Given the crucial role of this corticolimbic network in regulating emotional behavior, it is palpable that alterations in endocannabinoid signaling within any of these structures could have profound implications for the pathophysiological development of affective illnesses. Accordingly, local pharmacological augmentation of endocannabinoid signaling within discrete corticolimbic subregions may serve as a promising therapeutic strategy for the treatment of these debilitating disorders. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.