In this issue of Critical Care, Megarbane and colleagues present a case report of methadone-induced respiratory depression and conduct a toxicokinetic/toxicodynamic evaluation. An opioid-dependent patient receiving methadone maintenance treatment (daily dose 70 mg) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam. Significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg/hour. In patients receiving methadone maintenance treatment, an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence. However, few such patients experience episodes of life-threatening respiratory depression. Here, we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and, ultimately, to predict which patients are most likely to be affected.