The vast majority of epidemiological studies indicate that cannabinoids constitute the most frequently encountered psychoactive substances in the blood of drivers who are drug-impaired and/or involved in accidents, and thus cannabis must be considered a serious problem for traffic safety. In order to better understand its effects on cognitive functions involved in the short-term ability to drive, experimental research has been conducted based on laboratory, simulator, or on-road studies and, more recently, brain imaging. According to the results reviewed in the present chapter, cannabis use has been shown to impair actual driving performance by increasing lane weaving and mean headway. It also impairs cognitive functions, including working memory, motor inhibition, and divided attention. However, several factors, including history of cannabis use, routes of administration and dose ranges, as well as study designs (eg, treatment blinding), explain some discrepancies. Moreover, the neurobiological mechanisms underlying the effects of cannabis on safe driving remain poorly understood, as does the correlation between body fluids (blood, oral fluid) concentrations and psychoactive effects of THC and its main active metabolites.