Theoretical background: Considerable progress has been made in illuminating the neural basis of the compulsive use patterns characterizing substance use disorders. It has been suggested to utilize these findings to alleviate the health burden associated with substance use. Objective: We address how neuroimaging research can provide these benefits. Methods: Based on neurobiological models of addiction, we highlight neuroimaging research elucidating neural predictors of relapse and how treatments modify these markers. Results: With the focus on cue reactivity, brain activity related to the motivational salience of drugs and automatized use behaviors can predict relapse. Cue reactivity changes with abstinence, and it remains to be determined whether such changes confer periods of critical relapse susceptibility. Conclusions: Several established and emerging interventions modulate brain activity associated with drug value. However, executive deficits in addiction may compromise interventions targeting control-related prefrontal brain areas. Lastly, it remains more difficult to change the brain responses mediating habitual behaviors.