The US opioid crisis has rapidly escalated over the past 4 decades, with a shifting profile of available substances contributing to rising fatalities. Leading this crisis is illicitly manufactured fentanyl, now increasingly adulterated with xylazine, a veterinary sedative not approved for human use. Despite a greater awareness in recent years regarding the vital role of naloxone in preventing fatal cases of overdose, xylazine has been associated with a sharp increase in overdose-related deaths due to its potent central nervous system effects. Recent data suggest a significant spread of xylazine, underscoring the importance of strategies to counteract fentanyl and implement aggressive supportive care for xylazine-fentanyl toxicity. This combination, often undetectable by standard drug tests, presents challenges in diagnosis and treatment of overdoses. These challenges have become relevant among young adults, a demographic particularly affected, underscoring the need for harm reduction measures and further research into the shifting patterns of fentanyl-related intoxication across the United States.