Cigarette smoking is a major public health danger. Sex differences exist in the behavioral and molecular mechanisms underlying tobacco smoking, i.e., men tend to smoke for the reinforcing effects of nicotine whereas… women tend to smoke to regulate stress and mood. Smoking cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. The mesolimbic dopamine system drives the reinforcing effects of tobacco smoking and the mesocortical dopamine system is critical for inhibitory control, which is compromised by stress. We used positron emission tomography (PET) to capture the effects of smoking on both dopamine systems in humans, in vivo. First, we found that when male smokers smoked a cigarette during PET scanning, they released more dopamine in the reward region of the mesolimbic dopamine system while female smokers released more dopamine in the habit-formation region of the mesolimbic dopamine system. This finding is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. Next, we examined the mesocortical dopamine system and found that female smokers have a blunted or hypofunctioning dopamine response compared to male smokers and female nonsmokers. These findings demonstrate that tobacco smoking differentially affects both dopamine systems in men and women, suggesting a need for sex/gender-specific treatments.