Advances in neuropsychosis have concluded that addiction is a chronically relapsing brain disorder. Cue-, drug-and (or) stress- primed reinstatement play important parts on the development of drug abuse. Stress is a key factor in the acquisition and persistence to illicit drugs and psychostimulants such as cocaine, heroin, ketamine, alcohol and nicotine. When the access to the drug is prevented, the emergence of a negative emotional state will trigger the crucial neurochemical elements involved in the brain reward and stress systems. In this review, we will first discuss the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in the compulsive drug taking. The prominent components of stress-responsive system including CRH, vasopressin and glucocorticoid will be considered as the dark side drivers in addiction. And then we will reveal the essential mechanisms of propofol abuse as well as its association with HPA axis responsiveness. Propofol is a widely used intravenous anesthetic. However, in recently year’s propofol has been demonstrated as an addictive drug in anesthesiology. Converging evidence suggests the activation of mesocorticolimbic system and the interactions between the reward and stress system can partly illustrate the specific mechanisms of propofol abuse. Future directions in research are identified to increase understandings of the mechanisms by which stress may increase risks of drug addiction.