There is growing evidence that meditation practice can reduce the experience of pain. However, what is going on in the brain during meditation that causes this pain relief has been a mystery. We guessed that meditation might reduce pain by releasing natural brain chemicals called endogenous opioids. Endogenous opioids reduce pain via the same brain chemistry as morphine—essentially the brain’s natural morphine. We tested whether this natural morphine causes meditation’s pain relief by manipulating long-term meditators’ endogenous opioid activity during safe and temporary pain testing. We found that endogenous opioids are not the brain chemicals that meditation uses to reduce pain, making meditation different from most mental and emotional pain reduction strategies. We also found that meditation reduced pain even more when endogenous opioids were blocked. This pain relief enhancement during endogenous opioid blockade has never been seen before in a scientific study, and suggests that endogenous opioids might interact with other brain chemicals in previously undiscovered ways. In this way, studying the brain science of meditation is not only helping us understand meditation. It’s also helping us understand basic brain science in ways that could affect many aspects of health.