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Numerous factors are involved in the motivation to smoke and are associated with relapse, including stress, peer pressure, availability, menstrual cycle phase, and even weight management.1–5 However, smoking cue–induced and withdrawal-induced cravings are 2 of the major contributors to relapse.6–9 Inability to combat withdrawal-induced craving, which declines within a month,10 plays a role in early relapse. Nevertheless, smokers report that smoking cues (eg, seeing a pack of cigarettes, socializing with others who smoke, and even internal mood states repeatedly associated with smoking) can trigger relapse months or even years after quitting. Some smokers who are thought to possess high “cue re-activity” are especially vulnerable and have an increased probability of relapse initiated by exposure to smoking cues.11,12 Therefore, treatments that target cue reactivity are important, particularly for cue-vulnerable individuals, but the effect of existing smoking cessation medications on smoking cue reactivity has not been thoroughly investigated. Thus far, research has focused on reduction of withdrawal and nicotine reward, which are known mechanisms underlying the effectiveness of first-line smoking cessation agents, such as varenicline, nicotine replacement therapy, and bupropion hydrochloride.13–15 Varenicline is a first-line smoking cessation agent16,17 that acts as a partial agonist at α4β2 acetylcholine nicotinic receptors, with indirect agonist and antagonist actions on the mesolimbic dopamine system. During the absence of nicotine, as in a quit attempt, it acts as an agonist to mildly increase dopaminergic tone and reduce withdrawal-induced craving. When nicotine is available, as in a relapse, it acts as an antagonist, preventing nicotine-evoked dopamine release and effectively blocking the reward usually received from nicotine while smoking.15 It is thought that the dual agonist-antagonist properties of varenicline are key mechanisms underlying its clinical effectiveness. Various imaging modalities have observed a consistent neural substrate for cocaine, heroin, cigarette, and sexual cues.3,18–21 In studies of smoking cue reactivity, we characterized a neuroanatomical brain signature in response to exposure to smoking cues, independent of withdrawal, wherein the most profound effects were found in the interconnected ventral striatum (VS) and medial orbitofrontal cortex (mOFC).22–24 Our findings are in accordance with the substantial preclinical literature.25–27 Based on the evidence supporting a role for the medial ventral aspects of the mesolimbic system in drug cue reactivity, and varenicline’s actions to manipulate dopamine release, we hypothesized that chronic varenicline administration would suppress these responses; specifically, we hypothesized that varenicline would modulate activity in the mOFC, which is involved in sensory integration (representing the affective value of reinforcers) and decision making (for emotional rewards).28,29 Furthermore, we suspected that varenicline might diminish ventral striatal responses to cues because this region exerts strong control over emotional and motivational behavior, including craving.30,31 Preliminary data from our laboratory showed that varenicline selectively activated the lateral OFC (LOFC) in the brain at rest. Based on our data and the literature demonstrating that lateral pre-frontal regions are involved in regulating impulses, in reevaluating previously rewarded behavior, and in modulating downstream limbic regions involved in motivated behavior,29,32,33 we suspected that varenicline might enhance activity in lateral prefrontal regions. We predicted that varenicline-induced activation of the LOFC in the brain at rest would correlate with diminished neural responses during exposure to smoking cues. To quantify the effects of long-term administration of varenicline on the resting brain and on the brain’s responses during exposure to smoking cues, we implemented a laboratory model of conditioned responding and the technique of continuous arterial spin-labeled (CASL) perfusion functional magnetic resonance imaging (fMRI) to image nonabstinent smokers before and after a 3-week double-blind randomized placebo-controlled medication regimen. The importance of using nontreatment-seeking smokers in our paradigm is 2-fold. First, our goal was to determine if and how varenicline affected smoking cue reactivity independent of withdrawal (which can persist for up to a month) because it has been shown that withdrawal itself can affect brain activity.34 Second, it was important that varenicline-treated and placebo-treated groups had similar smoking characteristics because differences in smoking behavior modulate brain activity.35 Thus, issues related to withdrawal and quitting smoking, which might obviate accurate interpretation of the effects of varenicline on exposure to smoking cues, were minimized. Similar to positron emission tomography, perfusion fMRI is quantitative, providing a measure of cerebral blood flow in milliliters of blood per 100 g of tissue per minute,36 which facilitates the measurement of medication-induced neural modifications in the brain in response to tasks (cue exposure)23 and in the brain in the resting condition (without provocation)37 at successive time points. A pharmacological manipulation can have profound effects on the brain that cannot be observed using a relative measure such as blood oxygen level–dependent fMRI, which can only accurately examine changes that occur within a scanning session during a task or other provocation. Perfusion fMRI is reliable and reproducible following intervals as long as 7 weeks and is therefore ideal for longitudinal studies examining brain modifications induced by pharmacological agents.37