Fentanyl and non-pharmaceutical fentanyls (NPFs) have been responsible for numerous outbreaks of overdoses all over the United States since the 1970s. However, there has been a growing concern in recent years that NPFs are contributing to an alarming rise in the number of opioid-related overdoses.The authors conducted a narrative review of the published and grey literature on fentanyl and NPFs in PubMed, Google Scholar, and Google using the following search terms: "fentanyl", "non-pharmaceutical fentanyl", "fentanyl analogs", "fentanyl laced heroin" and "fentanyl overdose". References from relevant publications and grey literature were also reviewed to identify additional citations for inclusion.The article reviews the emergence and misuse of fentanyl and NPFs, their clinical pharmacology, and the clinical management and prevention of fentanyl-related overdoses.Fentanyl and NPFs may be contributing to the recent rise in overdose deaths in the United States. There is an urgent need to educate clinicians, researchers, and patients about this public health threat.