Mutations in the mu-opioid receptor--the primary site of action of opioid analgesics--are candidates for the variability of clinical opioid effects. This has been substantiated by recent advances in genetic research. A common mu-opioid receptor polymorphism was associated with higher demands for alfentanil or morphine for pain relief. It also decreased the potency of morphine for pupil constriction and experimental analgesia, but its molecular mechanisms are unclear. Another opioid receptor mutation greatly impaired receptor signalling in vitro, but is very rare. The accumulated evidence provides a solid basis for continuing research that should address the underlying molecular mechanisms and the role and benefits of OPRM1 genotyping for clinical pain therapy.