Cannabis is the most commonly used illicit drug worldwide and its use is associated with multiple adverse health effect including the risk of addiction. Identifying factors involved in cannabis use and abuse is critical for optimizing evidence-based prevention and treatment protocols. Similarly to other drugs of abuse, the prevalence of cannabis use and addiction differs between males and females, suggesting that sex is an important modulator of cannabinoid sensitivity. Accumulating evidence shows that the endocannabinoid system is sexually dimorphic and that sex hormones play a key role. Hormone-driven differentiation of the endocannabinoid system seems to provide a biological basis for sex differences in endocannabinoid-related behaviors, including reward-related behaviors. While sex differences in cannabinoid action are being increasingly studied in animals, controlled human studies are still limited. The endocannabinoid system is, for its intrinsic characteristics, a privileged target of the actions of both sex and anabolic-androgenic steroid hormones at different levels and, in turn, it can modulate the activity of sex hormones (Table 1). The observation that exposure to AAS causes dysfunction of the brain reward pathway in rats points to a potential risk factor for initiation of cannabis use, maintenance of regular use and development of CUD. The cross talk between endocannabinoid signaling and steroid hormones can occur differently in males and females, and many questions about underlying mechanisms remain unanswered, demanding further research in the field in an attempt to elucidate the basis of the sex differences often observed in cannabinoid sensitivity.