This chapter focuses on the accumulating evidence from preclinical, clinical and population studies that highly stressful situations and chronic stress increases addiction vulnerability, facilitating continued drug use and abuse and ultimately chronicity of addiction severity and relapse risk. Humans have long been known to use drugs and rewarding behaviors to modulate distress and emotions. Stress, trauma and negative emotional states challenge the individual to modulate and regulate these states. Stress can be mild/moderate in duration, or severe and extreme and these gradations in intensity contribute to the type of adaptation or coping behaviors that an individual may select to reduce the stress state. There is growing evidence that high uncontrollable stress alters activity of the prefrontal and other cortical brain regions that coordinate higher cognitive or executive control functions. Both early life stress and chronic stress are also known to significantly affect the mesolimbic dopamine pathways and play a role in drug self-administration.