Sex and gender have been gaining ever greater attention due to their associated risks, dynamics, patterns and protective factors underlying substance abuse and addiction. Such differentiations and the clarification of complexities thereof take on even greater relevance in light of drug abuse scope worldwide. According to the 2022 World Drug Report released by the United Nations Office on Drugs and Crime (UNODC), in 2020 an estimated 284 million people worldwide aged 15–64 had used a drug within the last 12 months. The authors have set out to shed a light on determinants and contributing factors of drug abuse based on sex and gender and outline policy and medicolegal remarks aimed at delineating sex- and gender-based approaches towards drug abuse therapeutic interventions that are both therapeutically and ethically/legally viable and grounded in an evidence-based set of standards. Neurobiological data suggest that estrogen may facilitate drug taking by interacting with reward- and stress-related systems. In animal research, the administration of estrogen increases drug taking and facilitates the acquisition, escalation, and reinstatement of cocaine-seeking behavior. From a medicolegal perspective, it is of utmost importance to take into account the whole picture constituting each patient profile, which certainly includes gender factors and contributors, when outlining a therapeutic approach. Failure to do so could lead to negligence-based malpractice allegations, in light of the scientific findings representing best practices with which clinicians need to comply when caring for SUD patients.