Important events in the history of driving under the influence of alcohol (DUI) and/or other drugs (DUID) are reviewed covering a period of approximately 100 years. This coincides with major developments in the pharmaceutical industry and the exponential growth in motor transportation worldwide. DUID constitutes an interaction between the driver, the motor-driven vehicle, and one or more psychoactive (mind-altering) substances. In this connection, it is important to differentiate between drugs intended and used for medical purposes (prescription or licit drugs) and recreational drugs of abuse (illicit drugs). All chemicals with a mechanism of action in the central nervous system (brain and spinal cord) are potentially dangerous to use when skilled tasks, such as driving, are performed. The evidence necessary to charge a person with drug-impaired driving has evolved over many years and initially rested on a drivers own admissions and observations made about the driving by police officers or eyewitnesses. Somewhat later, all suspects were examined by a physician, whose task was to ask questions about any recent ingestion of alcohol and/or other drugs and to administer various clinical tests of impairment. By the 1940s-1950s, the driver was asked to provide samples of blood, breath, or urine for toxicological analysis, although the test results served only to verify the type of drug causing impairment of the driver. The current trend in DUID legislation is toward zero-tolerance or concentration per se statutes, which are much more pragmatic, because behavioral evidence of impairment is no longer a lynchpin in the prosecution case. This legal framework puts considerable emphasis on the results of toxicological analysis; therefore, the methods used must be accurate, precise, and fit for forensic purposes. Many traffic delinquents charged with DUI or DUID suffer from a substance use and/or personality disorder, with high recidivism rates. In addition to conventional penalties and sanctions for drug-related traffic crimes, many offenders would probably benefit from a medical intervention, such as counseling, rehabilitation, and treatment for substance use disorder, which often coexists with a mental health problem.