The adulteration of xylazine, a veterinary sedative and α₂-adrenergic agonist, with illicit fentanyl has emerged as a profound public health problem in North America. This combination, dubbed ‘tranq dope’, foments greater overdose risk while causing crippling complications such as skin ulcers and sedation that defies naloxone reversal. This review has collated all available data on the fentanyl with xylazine overdose epidemic, including its epidemiology, toxicology, clinical effects, and a review of harm reduction strategies in the context of the United States and Canada. Data from the United States Drug Enforcement Administration, The Centers for Disease Control and Prevention and Health Canada suggest a significant concentration in Philadelphia, Maryland, Connecticut, Vermont, as well as in Canadian provinces Ontario (Toronto), British Columbia, and Alberta. The combination of xylazine with fentanyl has been shown to cause more severe respiratory depression, hypotension, and bradycardia than fentanyl used alone. Major gaps still persist in the absence of reversal agents, unusual clinical symptoms, and infrequent detection in standard tests. Thus, combating this urgent issue requires systems thinking integrating different but parallel disciplines including advanced monitoring, novel clinical structuring for preemptive measures, and focused scientific medicine analysis.