Stress has multifaceted effects on pain. On the one hand, it is a powerful inhibitor of nociception and inflammation; on the other hand, it contributes to enhanced pathological states including the establishment and continuation of chronic pain. These seemingly paradoxical effects can be better understood by investigating how stress-induced plasticity in particular brain circuitry contributes to the chronic pain state. This review presents the rationale and evidence for the interactions between stress and pain, emphasizing underlying mechanisms and putting forth the hypothesis that stress partly mediates the deleterious effects of pain on the corticolimbic system. First, a general description of the corticolimbic circuitry predisposing and amplifying chronic pain will be discussed, followed by an overview of the neurotoxic effects of stress hormones on this circuitry. Recent studies show that the resulting perturbations to these brain circuits have significant consequences both for chronic pain and for general regulation of the stress response, primarily through feedback mechanisms controlling the hypothalamic–pituitary–adrenal axis. This overlap in effected circuitry provides a key point of comparison between stress and pain, and the similarities between the plasticity induced by chronic pain and chronic stress will be examined here. Chronic pain patients have been shown to exhibit maladaptive stress responses in general and in response to pain; the cause of this response and its consequence on pain severity will then be reviewed. Finally, factors that have been shown to lead to resilience or vulnerability for chronic pain and maladaptive stress responses will be summarized.