Fentanyl has been implicated as a major contributor to the increased number of opioid overdose deaths. Surprisingly, little is known about the pharmacogenetic influences on fentanyl pharmacokinetics or pharmacodynamics. Pharmacogenetic studies of fentanyl are based largely on small sample sizes and have examined the potential association of only a small number of high frequency variants in selected candidate genes primarily with postoperative pain. Few data are available on low frequency variants, variants from racially/ethnically diverse populations, or on other phenotypes. Given the genetic diversity of low frequency variants, DNA sequencing may be needed to determine whether pharmacogenetic differences may contribute to lethal opioid overdoses.