In humans, as in animals, males and females are dissimilar in their genetic and hormonally driven behaviour; they process information differently, perceive experiences and emotions in different ways, and display diverse attitudes. In the human population, gender differences in the frequency and patterns of cannabis use have been identified in clinical studies and anecdotal observations, although the nature of these differences is still poorly explored. The motivations for smoking cannabis are also different between sexes, especially in adolescents. A number of potential factors that could provide a neurobiological basis for gender-based differences in cannabinoid addiction have been identified, among which are organizational and activational effects of gonadal hormones, socio-cultural factors, different stress responsiveness, and impulse-control ability, as well as different cannabinoid pharmacodynamic and pharmacokinetic effects in males and females. In this chapter, we review both clinical and laboratory-based research evidence revealing important sex-related differences in cannabinoid-induced effects on reward and motivation.