Introduction: The population of adults 65 years of age and older is growing at an exponential rate in the United States. The current generation of older adults is more mobile and driving much later in life compared to previous cohorts. While the current generation of older adults is living longer, they are not necessarily healthier. Older adults consume roughly 30% of all written prescriptions, are the largest consumers of over-the-counter medications, and report a higher prevalence of lifetime licit and illicit drug use compared to previous generations. There is concern that many older adults will drive while taking drugs-either illicit or licit-that will interfere with their ability to safely operate a motor vehicle. Licit and illicit drug use is largely understudied in this population of drivers, particularly in the United States.;Methods: This study employed a systematic review to discern which individual licit drugs were associated with increased risk/odds of motor vehicle collision, a cross-sectional analysis of a national traffic fatality database to discern which types of licit and/or illicit drugs and combinations were most prevalent among fatally injured senior drivers compared to middle-aged drivers, and a case-crossover study using electronic medical records to assess the risk that individual licit drugs pose to drivers 65 years of age and older in West Virginia who were admitted to medical treatment following a motor vehicle collision.;Results: Among the 53 specific medications investigated by the 27 studies included in the systematic review, 15 medications (28.3%) were associated with an increased risk of motor vehicle collision. The medications that were associated with an increased risk of collision were: Buprenorphine, Codeine, Dihydrocodeine, Methadone, Tramadol, Levocitirizine, Diazepam, Flunitrazepam, Flurazepam, Lorazepam, Temazepam, Triazolam, Carisoprodol, Zolpidem, and Zopiclone. In the cross-sectional analysis, licit and illicit drug use among senior drivers occurred in 17.8% of those tested. Among drug-positive senior drivers, benzodiazepines and narcotics were frequent. The rates of testing positive for any drug, multiple drugs, combined drug and alcohol, and alcohol use alone among seniors were 47% (Rate ratio, RR=0.53, 95% CI 0.50, 0.57), 57% (RR=0.43, 95% CI 0.39, 0.48), 88% (RR=0.12, 95% CI 0.10, 0.15) and 79% (RR=0.21, 95% CI 0.19, 0.24) less, respectively, compared to middle-aged drivers. In the case-crossover study, few drivers tested positive for drugs. Of those testing positive, benzodiazepines and opiates were the most common. After adjusting for the number of medications a driver was consuming during case and control periods, cases consuming Tramadol (Odds ratio, OR: 11.41; 95% CI 1.27, 102.15), were at a significantly increased risk of motor vehicle collision if they consumed these medications 14 days before the collision compared to control periods. Numerous other medications, including Clopidogrel, Gabapentin, Citalopram, Insulin, Hydrochlorothiazide, Metoprolol, Zolpidem, and Nitroglycerine, were trending towards being associated with motor vehicle collision, but were not found statistically significant.;Conclusions: The findings of this research pose numerous clinical and research implications. As many of the licit drugs included in this analysis are widely prescribed, patients should be informed that their driving ability may be affected. Further exploration into this area is research is necessary as older adults are choosing to maintain their mobility later in life.