Vulnerability to becoming a smoker, the likelihood of smoking in a given situation and individual differences in smoking patterns are influenced by complex interactions of nicotine with genetically influenced differences in brain functioning, psychological traits, learning and responses to contextual states. This review addresses these interactions using the recently developed Research Domain Criteria (RDoC) of the National Institute of Mental Health (NIMH) that provide new ways of classifying neuropsychiatric disorders based on basic dimensions across multiple units of analysis, from genes to neural circuits to behavior, that cut across disorders as traditionally defined. NIMH expects that the RDoC approach will lead to new and better-focused treatments. The RDoC research domains/constructs are: (1) negative valence systems (fear, anxiety and loss); (2) positive valence systems (reward learning and reward valuation); (3) cognitive systems (attention, perception, working memory and cognitive control); (4) systems for social processes (attachment formation, social communication, perception of self and perception of others), and (5) arousal/modulatory systems (arousal, circadian rhythm and sleep wakefulness). The smoker status and the acute effects of smoking/nicotine and smoking abstinence have well-established and significant effects on all of these systems, though the nuances of the subcategories articulated in the RDoC have only recently received attention in studies of smokers.