We have known the endogenous opioid peptide beta-endorphin for 20 years. Surprisingly, our knowledge of the physiological role of this peptide and its receptors in modulation of pain perception is still fragmentary. Whereas most studies have tried to elucidate the physiological role of beta-endorphin by reversing evoked responses by the opioid antagonist naloxone, this review focuses on quantification of release of beta-endorphin in the brain as the approach to define physiological and pathophysiological roles of beta-endorphin in relation to nociception. Using a lateral ventricle-cisterna magna perfusion model in the anesthetized rat, it was shown that depolarization of neurons in the arcuate nucleus of the hypothalamus, where beta-endorphin in produced, was followed by release of beta-endorphin to the cerebrospinal fluid compartment. Intense activation of spinal nociceptive pathways by intrathecal capsaicin injections also led to beta-endorphin release. It is concluded that there may still be good reason to quantify beta-endorphin in human cerebrospinal fluid to elucidate the role of beta-endorphin in pain perception.