Current trends indicate that approximately 500 million of the world's existing cigarette smokers will prematurely die of causes that could be prevented by treatment of their addiction to tobacco delivered nicotine. Initial pharmacologically based treatment offerings and approaches have proven the concept that increasing the accessibility and diversity of treatment modalities helps more people quit smoking. These treatments have also shown, however, that the vast majority of smokers continues to find treatment less attractive and less accessible than cigarettes whose appeal is constantly stimulated by new formulations, marketing strategies, and implied claims of reduced risk. There appears to be considerable untapped potential public health benefit, as well as commercial opportunity, for medication developers to reach an increasing fraction of smokers who find current treatments unacceptable, inaccessible, or ineffective. The global opportunities to serve public health via medication development are growing even more rapidly as country after country recognizes the impending economic and health care problems posed by tobacco dependence and are opening their doors to treatment. Three areas of medications development offer particular promise: new forms of nicotine delivery, non-nicotine based medications, and new indications to reach those who are unable or unwilling to completely quit. This article discusses the biobehavioral rationale for medication development, the opportunities, and some of the prominent technical and regulatory challenges.