The opioid epidemic has led to significant morbidity and mortality, with the introduction of fentanyl as an adulterant exacerbating overdose rates. The Drug Enforcement Agency (DEA) has recently identified a new threat: xylazine, a powerful animal sedative with a different mechanism of action compared to illicit opioids like heroin and fentanyl. Xylazine is often injected intravenously, often in combination with other drugs, particularly fentanyl, which prolongs the euphoric effects of fentanyl. Xylazine can cause adverse effects such as bradycardia, hypertension followed by hypotension, premature ventricular contractions, ataxia, slurred speech, sedation, and respiratory depression. There is no reversal agent for xylazine, unlike naloxone for opioid overdoses. The increasing use of xylazine, especially in combination with opioids, has led to a significant rise in overdose fatalities, with a 1200% increase in xylazine-related deaths. Xylazine is also highly toxic to the skin, causing severe abscesses, ulcers, and infections, and can lead to amputation. The lack of uniform screening for xylazine in medical examiners' reports further complicates the understanding of its prevalence and impact. Additional clinical studies are urgently needed to understand the pharmacological effects of xylazine in humans, formulate public health interventions, and implement harm reduction strategies. Xylazine's presence in the illicit drug market is widespread, with cases documented in Puerto Rico, Toronto, and Philadelphia, and its use is expected to spread further. Treatment for xylazine overdose primarily involves supportive care, including ventilation and hemodynamics management, as there are no FDA-approved medications for treating xylazine intoxication. Further research is essential to develop effective treatments and manage withdrawal symptoms.The opioid epidemic has led to significant morbidity and mortality, with the introduction of fentanyl as an adulterant exacerbating overdose rates. The Drug Enforcement Agency (DEA) has recently identified a new threat: xylazine, a powerful animal sedative with a different mechanism of action compared to illicit opioids like heroin and fentanyl. Xylazine is often injected intravenously, often in combination with other drugs, particularly fentanyl, which prolongs the euphoric effects of fentanyl. Xylazine can cause adverse effects such as bradycardia, hypertension followed by hypotension, premature ventricular contractions, ataxia, slurred speech, sedation, and respiratory depression. There is no reversal agent for xylazine, unlike naloxone for opioid overdoses. The increasing use of xylazine, especially in combination with opioids, has led to a significant rise in overdose fatalities, with a 1200% increase in xylazine-related deaths. Xylazine is also highly toxic to the skin, causing severe abscesses, ulcers, and infections, and can lead to amputation. The lack of uniform screening for xylazine in medical examiners' reports further complicates the understanding of its prevalence and impact. Additional clinical studies are urgently needed to understand the pharmacological effects of xylazine in humans, formulate public health interventions, and implement harm reduction strategies. Xylazine's presence in the illicit drug market is widespread, with cases documented in Puerto Rico, Toronto, and Philadelphia, and its use is expected to spread further. Treatment for xylazine overdose primarily involves supportive care, including ventilation and hemodynamics management, as there are no FDA-approved medications for treating xylazine intoxication. Further research is essential to develop effective treatments and manage withdrawal symptoms.