Evidence is accumulating that the etiology, epidemiology, consequences and mechanisms that underlie drug abuse are different in males and females. In this review, we present examples of sex differences in all phases of drug abuse, including acquisition, steady-state maintenance, escalation, dysregulation, withdrawal, relapse and treatment. Most reported findings are based on laboratory research in animals, but there are corroborating reports from human clinical and epidemiological studies. In all phases of drug abuse, females seem to be more sensitive to the rewarding effects of drugs than males, and estrogen is a major factor that underlies these sex differences.