Chronic stress, drug use, and vulnerability to addiction are closely linked. Stress is a well-known risk factor for addiction and relapse. Population-based and epidemiological studies have identified specific stressors and individual-level variables that predict substance use and abuse. Preclinical research shows that stress exposure enhances drug self-administration and reinstates drug seeking in drug-experienced animals. Stress affects the corticotropin releasing factor (CRF) and hypothalamic-pituitary-adrenal (HPA) axis, extrahypothalamic CRF, autonomic arousal, and central noradrenergic systems. These alterations affect the corticostriatal-limbic motivational, learning, and adaptation systems, including mesolimbic dopamine, glutamate, and gamma-amino-butyric acid (GABA) pathways, which are underlying pathophysiology associated with stress-related addiction risk. Regular and chronic drug use also affect these stress and motivational systems, impacting stress regulation, impulse control, and compulsive drug seeking and relapse susceptibility. Research gaps in understanding the association between stress and addiction are presented, with the hope that addressing these questions will influence new prevention and treatment strategies. Stress is defined as a process involving perception, appraisal, and response to harmful, threatening, or challenging events. Stress experiences can be emotionally or physiologically challenging and activate stress responses and adaptive processes to regain homeostasis. Examples of emotional stressors include interpersonal conflict, loss of relationship, death of a close family member, and loss of a child. Common physiological stressors include hunger or food deprivation, sleep deprivation or insomnia, extreme hyper- or hypothermia, and drug withdrawal states. Regular and binge use of many psychoactive drugs serve as pharmacological stressors. Stress can include "good stress," which is based on external and internal stimuli that are mild/moderately challenging but limited in duration and results in cognitive and behavioral responses that generate a sense of mastery and accomplishment. However, prolonged, repeated, or chronic stress increases the uncontrollability and unpredictability of the stressful situation, lowering the sense of mastery or adaptability, and increasing the magnitude of the stress response and risk for persistent homeostatic dysregulation. Stress and emotions are closely related to adaptive behavior. The term "stress" refers to processes involving perception, appraisal, and response to harmful, threatening, or challenging events or stimuli. Stress experiences can be emotionally or physiologically challenging and activate stress responses and adaptive processes to regain homeostasis. Examples of emotional stressors include interpersonal conflict, loss of relationship, death of a close family member, and loss of a child. Common physiological stressors include hunger or food deprivation, sleep deprivation or insomnia, extreme hyper- or hypothermia, and drug withdrawal states. In addition, regular and binge use of many psychoactive drugs serve as pharmacological stressors. This kind of conceptualization allows the separate consideration of (1) internal and externalChronic stress, drug use, and vulnerability to addiction are closely linked. Stress is a well-known risk factor for addiction and relapse. Population-based and epidemiological studies have identified specific stressors and individual-level variables that predict substance use and abuse. Preclinical research shows that stress exposure enhances drug self-administration and reinstates drug seeking in drug-experienced animals. Stress affects the corticotropin releasing factor (CRF) and hypothalamic-pituitary-adrenal (HPA) axis, extrahypothalamic CRF, autonomic arousal, and central noradrenergic systems. These alterations affect the corticostriatal-limbic motivational, learning, and adaptation systems, including mesolimbic dopamine, glutamate, and gamma-amino-butyric acid (GABA) pathways, which are underlying pathophysiology associated with stress-related addiction risk. Regular and chronic drug use also affect these stress and motivational systems, impacting stress regulation, impulse control, and compulsive drug seeking and relapse susceptibility. Research gaps in understanding the association between stress and addiction are presented, with the hope that addressing these questions will influence new prevention and treatment strategies. Stress is defined as a process involving perception, appraisal, and response to harmful, threatening, or challenging events. Stress experiences can be emotionally or physiologically challenging and activate stress responses and adaptive processes to regain homeostasis. Examples of emotional stressors include interpersonal conflict, loss of relationship, death of a close family member, and loss of a child. Common physiological stressors include hunger or food deprivation, sleep deprivation or insomnia, extreme hyper- or hypothermia, and drug withdrawal states. Regular and binge use of many psychoactive drugs serve as pharmacological stressors. Stress can include "good stress," which is based on external and internal stimuli that are mild/moderately challenging but limited in duration and results in cognitive and behavioral responses that generate a sense of mastery and accomplishment. However, prolonged, repeated, or chronic stress increases the uncontrollability and unpredictability of the stressful situation, lowering the sense of mastery or adaptability, and increasing the magnitude of the stress response and risk for persistent homeostatic dysregulation. Stress and emotions are closely related to adaptive behavior. The term "stress" refers to processes involving perception, appraisal, and response to harmful, threatening, or challenging events or stimuli. Stress experiences can be emotionally or physiologically challenging and activate stress responses and adaptive processes to regain homeostasis. Examples of emotional stressors include interpersonal conflict, loss of relationship, death of a close family member, and loss of a child. Common physiological stressors include hunger or food deprivation, sleep deprivation or insomnia, extreme hyper- or hypothermia, and drug withdrawal states. In addition, regular and binge use of many psychoactive drugs serve as pharmacological stressors. This kind of conceptualization allows the separate consideration of (1) internal and external