Warnings in Europe signal a rise in illicitly-manufactured fentanyl and other high potency synthetic opioids which could destabilize drug markets, strain health systems, and escalate harms of substance use and death. Here, we provide an overview of fentanyl in North America, drawing implications for Switzerland. Fentanyl withdrawal starts sooner, is more severe, and has worse anxiety and pain. Clinical care includes aggressive use of full agonist opioids, opioid agonist therapies (OAT) and adjunctive medications for acute withdrawal, and a need for low-threshold, readily accessible OAT to engage patients and mitigate harms. The US experience suggests the importance of widespread naloxone distribution, peer-based initiatives, early warning systems, and partnerships across patient-groups, healthcare systems, and public health.