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Background Overdose deaths related to illegal drugs in North American markets are now dominated by potent synthetic opioids such as fentanyl, a circumstance foreshadowed by often‐overlooked events in Estonia since the turn of the century. Market transitions generate important and far‐reaching implications for drug policy. Argument and analysis The supplier‐driven introduction of illegally manufactured synthetic opioids into street opioids is elevating the risk of fatal overdose. Using the most recent overdose mortality and drug seizure data in North America, we find that overdose deaths and seizures involving synthetic opioids are geographically concentrated, but this might be changing. Examination here suggests that in some places fentanyl and its analogues have virtually displaced traditional opioids, such as heroin. The concealing of synthetic opioids in powders sold as heroin or pressed into counterfeit medications substantially increases harms. The nature and scale of the challenge posed by synthetic opioids is unprecedented in recent drug policy history. Conclusions There is urgent need for policy and technological innovation to meet the challenges posed by illegally produced synthetic opioids. Novel interventions worth examining include supervising drug use, proactively deterring on‐line distribution and new technologies aimed at improving transparency, such as point‐of‐use drug content testing. Continuing to approach this problem only with existing policies and available methods, such as naloxone, is unlikely to be enough and will result in many premature deaths.

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