This book includes the latest discoveries on the interactions of stress neurobiology and addiction. It addresses the role of stress in addiction vulnerability, maintenance, and relapse from basic and clinical perspectives. This chapter highlights some of these discoveries and relates them to conceptual framework linking stress and addiction processes. There is compelling evidence of the importance of considering stress when addressing addiction vulnerability and tackling issues related to treatment and recovery. The chapter discusses in detail components of a multivariate working model, focusing first on the role of stress in addiction vulnerability and the physiological mechanisms mediating this risk. It then highlights the role of stress in maintaining addiction and in precipitating relapse. Next, it highlights issues that moderate the interaction of stress and addiction, including genetics, sex, and coping style. It briefly discusses how impulsivity and cognitive deficits may mediate the effects of stress on addiction processes. Finally, the chapter outlines a research agenda for the future that builds on the current state of knowledge and advances it toward more discoveries to improve diagnosis and treatment of addictions.