Experiencing stressful life events is reciprocally associated with substance use and abuse. The nature of these relationships varies based on the age of stress exposure and stage of substance use involvement. This chapter reviews the developmental and biological processes involved in the relationship of stress exposure and substance use initiation, substance use maintenance and relapse, and response to substance abuse treatment. Special emphasis is given to describing the various stress-related mechanisms involved in substance use and abuse, highlighting the differences between each of these phases of drug use and drawing upon current research to make suggestions for treatments of substance use disorder (SUD) patients. Stress is inherent to the experience of life and, in many situations, unavoidable. Through ongoing research and treatment development, there is the potential to modify the relationship of stress with ongoing substance use and abuse.