Drug markets evolve faster than guidelines, and xylazine has moved from regional curiosity to a widespread adulterant that complicates overdose response and wound care. Xylazine and Polysubstance Trends equips teams to read local supply signals, adjust clinical pathways, and communicate risk without losing trust. We begin with the pharmacology and kinetics that matter at the bedside: xylazine’s α2-adrenergic effects, sedation, bradycardia, hypotension, and prolonged intoxication that can obscure or outlast opioid effects. In polysubstance mixes—fentanyl, benzodiazepines, stimulants—signals blur; naloxone still treats opioid respiratory depression, but post-reversal sedation or hypotension can persist from xylazine. We map a practical exam: vitals, pupil findings, glucose, temperature, skin checks for necrotic-appearing lesions, and attention to aspiration risk. Field care emphasizes airway, oxygenation, naloxone as indicated, and transport; ED care adds fluids, vasopressor readiness if severe hypotension, and wound debridement pathways. We detail nursing protocols for frequent repositioning, pressure offloading, and infection prevention when skin is fragile. Harm-reduction conversations must be frank and nonjudgmental: source uncertainty, test strip availability where legal, safer-use steps, and early presentation for wounds. For OUD, MOUD remains lifesaving; we discuss induction amid sedation, bridging plans, and how to counsel that naloxone is still essential even if “it didn’t wake them up.” Surveillance matters: track local EMS signals, assay reports where available, and syndromic trends in sedation and wound patterns. Equity threads include language access, rural transport, and stigma that keeps people away from clinics. We prepare teams to align law enforcement, EMS, shelters, and outpatient addiction care so messaging and pathways are consistent. With clear eyes and coordinated practice, Xylazine and Polysubstance Trends, the rapid knowledge exchange at a xylazine conference, and core treatment anchors like MOUD help convert chaotic scenes into safer, more predictable care.