Nicotine is the primary compound that maintains tobacco smoking behavior, and nicotine reinforcement may be related to its discriminative stimulus effects. Nicotine in novel form, isolated from tobacco smoke, is often reinforcing in men but not in women, and clinical trials with nicotine replacement via gum or patch have often shown less efficacy in women vs. men trying to quit smoking. We hypothesize that this sex difference in nicotine reinforcement or clinical efficacy may be related to reduced intensity of nicotine's discriminative stimulus effects in women. Using formal drug discrimination procedures, we have found in several studies that discrimination responding across nasal spray nicotine doses tends to be flatter for women than men (i.e., sex x dose interaction), suggesting reduced sensitivity to changes in dose. Results from the field of psychophysiology, involving detection of physiological changes, are generally consistent with our findings, and suggest that the environmental context accompanying physiological change is important in understanding this sex difference. The implications of this sex difference for smoking cessation treatment and future research directions are presented.