Xylazine is a nonopioid veterinary anesthetic and sedative that is increasingly detected in the illicit drug supply in the United States. Data indicate a striking prevalence of xylazine among opioid-involved overdose deaths. The emergence of xylazine in the illicit drug supply poses many unknowns and potential risks for people who use drugs. The public health system needs to respond by increasing testing to determine the prevalence of xylazine, identifying its potential toxicity at various exposure levels, and taking mitigating action to prevent harms. Currently, there is little testing capable of identifying xylazine in drug supplies, which limits the possibility of public health intervention, implementation of harm reduction strategies, or development of novel treatment strategies. (Am J Public Health. 2022;112(8):1212–1216. https://doi.org/10.2105/AJPH.2022.306881 )