Substance use disorders are estimated to affect 20.4 million individuals in the United States with the financial cost of alcohol and substance addiction calculated at half a trillion dollars per year. Drug and alcohol addictions are now recognized as chronic, relapsing disorders, with approximately 60% of individuals relapsing following extended periods of sobriety. Research has identified two major sources of risk for relapse: 1) reward-related factors associated with increased wanting or desire for the substance of abuse; and 2) cognitive control-related factors linked to both the deliberate suppression of these desires as well as reduced attention to environmental and internal triggers. Although studies have investigated each of these systems independent of the other, few have effectively examined the relative contributions of reward- and cognitive control-related factors to relapse. Fewer still hav combined the use of targeted behavioral and neuroimaging measures to examine the underlying neurobiology of risk for relapse in substance use disorder. Furthermore, relapse studies rarely examine vulnerabilities across substances of abuse in poly-substance abusers, preferring to study one primary substance. Poly-substance abuse is arguably far more representative of real-world addiction. The proposed project will use clinically relevant functional neuroimaging and behavioral measures of pure cognitive control and reward-related processes, as well as the relationship between the two, to assess the strongest predictors of relapse in individuals with poly-substance use disorder. Furthermore, unlike many other imaging studies of relapse we will recruit participants in a controlled treatment setting, where we can more reliably ascertain not only the status of participants (relapse vs. no relapse) but also the number of days to relapse. Our goal is to determine whether cognitive control- versus reward-related factors, or their combination, is the stronger predictor of relapse in poly-substance use disorder. Data generated by this R21 will have clinical relevance by offering treatment providers tools to effectively tailo addiction treatments to specific neurobiological vulnerabilities. Results from this proposed study represent an important first step in the development of a longitudinal research program aimed at investigating the neural and psychological risk factors for developing and maintaining substance use disorder in poly-substance abusers. This project would provide pilot data for a larger RO1 proposal to investigate relapse in greater detail, including more comprehensively probing mediators such as social, psychological and clinical risk factors. The goals of this proposal align directly with the interests of CRAN (Collaborative Research on Addiction at NIH) by studying individuals with poly-substance use disorder.