A variety of physical and psychological stressors induce analgesia by activating descending systems that project from the brain to the spinal cord. This stress-induced analgesia (SIA) is mediated by distinct opioid- and non-opioid-dependent mechanisms. New evidence suggests that non-opioid SIA is mediated by two independent endocannabinoids within the midbrain. Furthermore, novel agents that disrupt breakdown of these endocannabinoids enhance non-opioid SIA and pave the way for novel therapies.