Liability to spontaneous and experimental pain is genetically determined and there is considerable variability in the antinociceptive effects of drugs commonly used in treating pain conditions and migraine attacks. The causes for variability involve still unknown genetic aspects. Recently, a third gene, SCN1A, was discovered as a cause of familial hemiplegic migraine (FHM). Recent advances in the genetics of pain and pain disorders include the discovery of the role of the sodium ion channel SCN9A in neuropathic pain as well as in inability to experience pain, and of GTP cyclohydrolase (GCH1) in setting the sensitivity to pain in normal individuals and modulating liability to chronic pain. Catechol-O-methyltransferase (COMT) and the cytochrome P450 variant allele CYP3A5 modulate the genetic response to opioid medications in humans. Variability in drug pharmacokinetics and adverse drug reactions of pain medications are also very much related to genetic variation, especially in CYP genes. Pharmacogenomic studies of headache and pain are still in their infancy, but these recent advances in the genetics of migraine and pain arguably hold the promise of individualised treatments and prevention of adverse drug reactions.