Depending on its nature, duration, and intensity, stress can exert potent and bidirectional modulatory effects on pain, either reducing pain (stress-induced analgesia) or exacerbating it (stress-induced hyperalgesia). The descending pain pathway has been implicated in both stress-induced analgesia and stress-induced hyperalgesia. The endogenous opioid system is widely distributed throughout the descending pain pathway and regulates nociceptive signaling, emotionality, and the response to stress. Here we review the evidence for a key role of the endogenous opioid system in stress-induced modulation of pain in rodents and humans. Understanding the neurobiological mechanisms underlying opioidergic regulation of stresspain interactions may help in identifying novel therapeutic strategies for the improved treatment of comorbid pain and stress-related disorders.