Abstract Tobacco addiction is the largest single public health issue in America. In veterans, smoking is particularly prevalent and is associated with several problems including cancer risk, depression and other addiction comorbidities, and heart disease, among others. Although most smokers, including those in the military express a desire to quit, most return to smoking within days of cessation trials, mainly because of withdrawal symptoms. We and others have shown that the habenula, a small and understudied brain region may be critical for tobacco addiction and nicotine withdrawal symptoms. The habenula integrates several types of input and modulates the activity of several midbrain areas (ventral tegmental area/substantia nigra compacta, raphe nucleus, locus coeruleus and interpeduncular nucleus). Upon negative information, increased activity in the habenula may elicit negative feelings, depressed mood and enhanced arousal and anxiety. This system is present in even lower animal forms because it is necessary to allow learning from behavioral mistakes. We propose to use a multimodal imaging strategy in veteran smokers and non-smokers to study the habenular system. Based on our own preliminary data, we postulate that smokers will show decreased habenular fibers when compared to non-smokers. In addition, we postulate that abstinent veteran smokers will show enhanced habenular activity upon disappointing events. That could help explain several aspects of tobacco addiction: if the habenula is more active during abstinence, that would explain why people relapse: trying to quit could be similar to a continuous state of disappointment that would subside by smoking again. Importantly, tobacco smoke has a genetic component. Our data shows that a variant that increases the risk to become a smoker is also associated with increased habenular activity during disappointing events under abstinence. Thus, we postulate that upon cessation trials, most people return to smoke to suppress the negative affect originated in the habenula. This effect would be stronger in people with high genetic risk to become a smoker. We propose to study habenular activity (using functional MRI), habenular functional connectivity (using resting state functional MRI) and habenular white matter integrity (using diffusion tensor imaging) in non-smokers and in sated and abstinent tobacco smoking veterans. In addition, we will genotype the single nucleotide polymorphism rs16969968, which is associated to tobacco abuse, and which have preliminary shown that is also associated to increased habenular activity during abstinence. The innovative aspect of this research is clear: no one has studied the habenula in addicted veterans. The relevance is potentially large: if our hypothesis is correct and the habenula is abnormal in tobacco dependent veterans, that would imply that the way the addicted brain integrates information about reward, decision making, movement, and other modalities is impaired, and likely dependent on satiety status. This may have enormous implications for the field. Although not immediately applicable, if our hypotheses are correct, the development of anti-tobacco therapies should radically change. In the future, we hope to be able to customize anti-tobacco therapies using genetic and mechanistic information.