Road trac accidents are largely determined by human errors in information processing and attention. Attentional functions constitute a vulnerable link in the human information processing chain. Three distinct attentional brain mechanisms are described that are considered to be involved in the supply of nervous energy for information processing. Arousal, phasic physiological responses to novel stimuli; Activation, tonic physiological readiness to respond; and Eort, the voluntarily exerted coordination between arousal and activation. These energy supply systems are mainly driven by noradrenergic, dopaminergic and cholinergic neurotransmission, respectively. Furthermore, they are aected by a behavioural inhibition system controlled by serotonin. The histamine neurotransmitter system is also associated with behavioural activation, whereas the neurotransmitter GABA has an inhibitory in¯uence on the noradrenergic, dopaminergic and cholinergic systems. It is argued that the eects of drugs on driving can be predicted in terms of their eects on these neurochemical systems. Drugs that decrease noradrenaline-, acetylcholine-, dopamine-and histamine-neurotransmitter turn-over impair dierent facets of attention. GABAergic drugs are sedative, while serotonergic drugs seem to in¯uence attention in a more subtle manner. Any pharmacological intervention on one or more of these systems via medicinal or other psychoactive drugs, can alter, and often impair, driving performance. The assessment of behavioural, psychophysiological and pharmacological markers of the attentional systems during driving performance may provide clues for the answer to the question how, rather than if, drugs have an in¯uence on driving performance.