The opioid epidemic in the United States has evolved over the years, with the substances and adulterants involved changing over time. Fentanyl has increasingly been found in the drug supply, contributing to a dramatic rise in overdose deaths. More recently, the veterinary drug Xylazine has emerged as an additive to not only fentanyl but also other drugs of misuse, resulting in a growing number of overdose deaths nationwide. Given that many people are not aware that the drugs they are using contain Xylazine, these mixtures are particularly concerning. This edition of Clinical Insight explores what Xylazine is, its effects, and the challenges it presents within the illicit drug supply.