Background: People commonly use psychoactive substances to increase physical and psychological pleasure. Neuroadaptations in the brain’s reward system coupled with changes in social functioning and networking resulting from chronic substance use impede the ability to derive pleasure from non-substance related activities.Objective: We elucidate and validate the hypothesis that treatments for substance use disorders would potentially have a stronger and broader impact by helping recipients to experience pleasure as part of an expansive focus of increasing adaptive functioning, well-being, and personal fulfillment and actualization. Method: We have organized and integrated relatively sparse and disparate theory and research to describe a multi-stage model linking pleasure and substance use. We review research on pleasure in the context of treatment for substance use, and describe future research directions. Results: Our model integrates several independent research programs with prominent theories and models of substance dependence that together provide evidence that pleasure, or lack thereof, is a risk or protective factor for initiating, escalating and maintaining substance use and substance use disorders. Pleasure is an overlooked but potentially high-yield target of existing evidence-based treatments. Conclusion: Research is needed to investigate the relation between pleasure and substance use, and existing and newly developed treatments that have the potential to increase pleasure. By increasing pleasure such treatments have the potential to help recipients to live fuller and richer lives. Integration of pleasure into existing treatments has compelling transdiagnostic implications for individuals at any point along a substance use severity continuum.