Considering its pervasive and uncontrollable influence in drug addicts, understanding the neurobiological processes through which stress contributes to drug use is a critical goal for addiction researchers and will likely be important for the development of effective medications aimed at relapse prevention. In this paper, we review work from our laboratory and others focused on determining the neurobiological mechanisms that underlie and contribute to stress-induced relapse of cocaine use with an emphasis on the actions of corticotropin-releasing factor in the ventral tegmental area (VTA) and a key pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine and beta adrenergic receptors. Additionally, we discuss work suggesting that the influence of stress in cocaine addiction changes and intensifies with repeated cocaine use in an intake-dependent manner and examine the potential role of glucocorticoid hormones in the underlying drug-induced neuroadaptations. It is our hope that research in this area will inform clinical practice and medication development aimed at minimizing the contribution of stress to the addiction cycle, thereby improving treatment outcomes and reducing the societal costs of addiction.