Addition is a chronic relapsing illness affected by multiple social, individual and biological factors that significantly impact course and recovery of the illness. Stress interacts with these factors and increases addiction vulnerability and relapse risk, thereby playing a significant role in the course of the illness. This paper reviews our efforts in developing and validating laboratory models of stress and drug cue-related provocation to assess stress responses and stress-related adaptation in addicted individuals compared with healthy controls. Empirical findings from human laboratory and brain imaging studies are presented to show the specific stress-related dysregulation that accompanies the drug-craving state in addicted individuals. In order to adequately validate our laboratory model, we have also carefully examined relapse susceptibility in the addicted individuals and these data are reviewed. The overarching goal of these efforts is to develop a valid laboratory model to identify the stress-related pathophysiology in addiction with specific regard to persistent craving and compulsive seeking. Finally, the significant implications of these findings for the development of novel treatment interventions that target stress processes and drug craving to improve addiction relapse outcomes are discussed.