This review focuses on the role of motor vehicles in the prevention of alcohol-related fatalities in the United States. Since alcohol significantly affects brain function, it is natural to make drivers the prime targets for impaired-driving-prevention programs. However, the prevalence, design, ease of operation, and safety features of motor vehicles, as well as state regulations of their operation, have an important influence on crash occurrences, particularly those involving alcohol. This review begins with a discussion of why the automobile became the central technological device in the alcohol-related fatality problem and then moves on to an overview of motor vehicle safety programs that have impacted impaired driving. The article then presents an extended discussion of the effectiveness of vehicle-based, alcohol-detecting ignition interlock devices (interlocks), which provided the principal specific vehicle-based effort in the 20th century to separate alcohol consumption from driving. The review ends with a commentary on the issues that will arise in managing operator impairment in autonomous (self-driving) vehicles-the probable principal 21st-century effort to reduce impaired driving and eliminate alcohol-related crashes by minimizing the role of the driver.