Purpose of review <p>This review synthesizes the epidemiological, pharmacological, and clinical dimensions of opioid–stimulant co-use and contamination, the growing predominance of smoking as a route of administration, and the implications of these trends for clinical practice and public health policy.</p> Recent findings <p>Recent surveillance data have revealed that more than 90% of fentanyl-positive specimens also contain stimulants, indicating that co-exposure, whether intentional or through supply-level contamination, has become the norm rather than the exception. In parallel, smoking has surpassed injection drug use as the dominant route of opioid/fentanyl administration in several regions of the United States. These use patterns have compounded both the risk profile and clinical presentation.</p> Summary <p>Opioid–stimulant co-use continues to reshape the overdose crisis, and effective responses will require pharmacological options and care-delivery models that address both substance classes.</p>