The present paper proposes a model for the identification and the validation of brain processes and mechanisms underlying smokers' cue reactivity. Smoking behaviour is maintained by the reinforcing properties of nicotine, but it was also proposed that nicotine enhances the conditioned value of smoking and nicotine-associated stimuli. In fact, it is widely reported that the exposure of smokers to smoking/nicotine-associated stimuli induces cue reactivity, which is a vast array of physiological, psychological and behavioural responses. Imaging studies are revealing neuroanatomical correlates of cue reactivity in brain areas involved in motivational, emotional, cognitive processes and in their integration. Behavioural studies in laboratory animal models have shown analogies between the effects of nicotine-associated stimuli and cue reactivity effects in smokers. Lesion and mapping studies with nicotine reported brain activation patterns in cortico-limbic areas similarly to those obtained with imaging studies in humans. Although only limited studies have been done with nicotine-associated stimuli in animals, the identification of molecular mechanisms underlying other drugs of abuse-associated cue effect may help to propose potential common molecular mechanisms for nicotine cues. These findings suggest that smoking/nicotine-associated stimuli are processed at two levels: (i), bottom-up, automatic processing in a parallel fashion through ascendant pathways, to activate attentional functions; (ii), top-down, in a serial fashion from cortical areas, to modulate sensory inputs and motor control. It appears that nicotine increase information processing at both levels so as to establish and to amplify the conditioned value of smoking cues.