Pharmacotherapies for smoking cessation that can be used in a minimal behavioral intervention setting are urgently needed. The studies described in this article show that the nicotinic antagonist mecamylamine is efficacious when administered in combination with nicotine replacement. Mecamylamine and nicotine have been shown to act in concert to attenuate the rewarding effects of cigarette smoking, reduce craving, and suppress ad lib smoking. Moreover, long-term abstinence rates following nicotine/mecamylamine treatment are roughly two to three times higher than with standard nicotine replacement therapy using nicotine skin patches. In one study, the initiation of mecamylamine treatment prior to the target quit-smoking date was shown to be critical in promoting subsequent continuous abstinence from smoking. The main interpretation of this finding is that smoking in the presence of blockade of reward promotes extinction of smoking behavior, raising the likelihood of successful smoking cessation. Directions for future research are also discussed, including mechanistic studies of nicotinic receptor subtypes affected by nicotine and mecamylamine, as well as assessment of the optimal timing, doses, and route of administration of the two drugs in smoking cessation treatment. Overall, the results show that two classic approaches to the treatment of drug dependence, substitution, and blockade, are not mutually exclusive and in fact can be combined fruitfully in the treatment of nicotine addiction.