Stress plays an important role in drug addiction. It can trigger relapse in abstinent addicts, and both in the everyday world and in the laboratory, a stressor can induce drug craving. Drug cues, such as the sight of drug, can also trigger subjective craving and relapse, and this effect may be amplified by stress. Underpinning this interaction may be the fact that stress and reward-predicting drug cues act on overlapping brain regions. We exposed 15 smokers undergoing functional magnetic resonance imaging to a psychosocial stressor, the Montreal Imaging Stress Task, followed by drug cues consisting of video clips of smokers. In a separate session similar video clips were shown after a non-stress control task. We observed significantly decreased neural activity during stress in the hippocampus, amygdala, bed nucleus of the stria terminalis, hypothalamus and nucleus accumbens. Following stress there was an increased neural response to drug cues in the medial prefrontal cortex, posterior cingulate cortex, dorsomedial thalamus, medial temporal lobe, caudate nucleus, and primary and association visual areas. These regions are thought to be involved in visual attention and in assigning incentive value to cues. Stress-induced limbic deactivation predicted subsequent neural cue-reactivity. We suggest that stress increases the incentive salience of drug cues.