BACKGROUND/IMPORTANCE: Driving under the influence of drugs (DUID) refers to operating a vehicle after consuming drugs or medications other than alcohol that impair the ability to drive safely. There is no consensus on legal limits for drug intoxication while driving in the USA. Balancing the benefits of prescription medications, such as opioids, with traffic safety remains an ongoing public health challenge. OBJECTIVE: This article examines DUID policy and provides recommendations for policy improvement and unification grounded in scientific evidence on opioid-related impairment and driving risks. EVIDENCE REVIEW: A literature review of epidemiologic data, psychomotor effects, and public policy related to opioid use and driving was conducted. A total of 38 epidemiological studies, 21 studies on psychomotor effects, and pertinent laws and policies were reviewed. FINDINGS: Epidemiological data reveal an increasing prevalence of opioid-positive drivers and an association between opioid use and elevated risk of motor vehicle collisions. Psychomotor studies show mixed results, with some indicating impairment in opioid users and others suggesting minimal effects on driving ability. State laws regarding DUID remain heterogeneous, with trends toward expanded testing powers, lower impairment thresholds, and limitations on prescription-based defenses. The lack of standardized opioid testing limits and inconsistent policy approaches across states hinder effective management of opioid-related impaired driving. CONCLUSIONS: A balanced public health approach can reduce opioid-involved crashes through education, prevention, enhanced enforcement tools, and rehabilitation. In drafting future DUID laws, policymakers must analyze evolving opioid research when balancing the pain relief of opioids with public roadway safety.