The prevalence of overdose deaths from opioids is still generally increasing throughout the world. Heroin is still the predominant illicit opioid of interest to toxicology laboratories because of its continuing widespread availability and its ability to elicit respiratory depression and coma. In many countries methadone continues to play a major role in cases of drug toxicity because of its large-scale use to treat opioid dependency and its high potency and long duration of action. Increasingly, buprenorphine is being used as an alternative pharmacotherapy, and although apparently safer than methadone, it still has an inherent risk of toxicity when used with CNS depressants such as benzodiazepines or when injected. Morphine continues to be the dominant analgesic; however, oxycodone, hydromorphone, hydrocodone, and fentanyl are increasingly being used and will require increasing efforts by toxicology laboratories to ensure that these substances are adequately covered by testing programs.