Epidemiological studies suggest that Cannabis use during adolescence confers an increased risk for developing psychotic symptoms later in life. However, despite their interest, the epidemiological data are not conclusive, due to their heterogeneity; thus modeling the adolescent phase in animals is useful for investigating the impact of Cannabis use on deviations of adolescent brain development that might confer a vulnerability to later psychotic disorders. Although scant, preclinical data seem to support the presence of impaired social behaviors, cognitive and sensorimotor gating deficits as well as psychotic-like signs in adult rodents after adolescent cannabinoid exposure, clearly suggesting that this exposure may trigger a complex behavioral phenotype closely resembling a schizophrenia-like disorder. Similar treatments performed at adulthood were not able to produce such phenotype, thus pointing to a vulnerability of the adolescent brain towards cannabinoid exposure. The neurobiological substrate of the adolescent vulnerability is still largely unknown and experimental studies need to elucidate the cellular and molecular mechanism underlying these effects. However, the few data available seem to suggest that heavy adolescent exposure to cannabinoids is able to modify neuronal connectivity in specific brain areas long after the end of the treatment. This is likely due to disruption of maturational events within the endocannabinoid system during adolescence that in turn impact on the correct neuronal refinement peculiar of the adolescent brain, thus leading to altered adult brain functionality and behavior.