Driving under the influence of alcohol has been shown to increase the risk of involvement in road traffic collisions (RTCs) however, less is known about the effects of illicit drugs, and a clear correlation between drug concentrations and RTC risk is still debated. The goal of this narrative review is to assess the current literature regarding the most detected psychoactive drugs in RTC (ethanol, amphetamines, cannabis, opioids and cocaine), in relation to driving performance. Evidence on impaired driving due to psychoactive substances, forensic issues relating to the assessment of the impact of drugs, blood cut-off values proposed to date as well as scientific basis for proposed legislative limits are discussed. At present there is no unequivocal evidence demonstrating a clear dose/concentration dependent impairment in many substances. Per se and zero tolerance approaches seem to have negative effect on drugged driving fatalities. However, the weight of these approaches needs further investigation.