In this paper it is argued that drugs of abuse act on specific neurotransmitter pathways and by this mechanism elicit neurochemical changes that mimic some aspects of the overall pattern of the neurochemical effects of natural rewarding stimuli. Thus, drugs of abuse are biochemically homologous to specific aspects of natural rewarding stimuli. The behavioral similarity between drugs of abuse and natural stimuli, including that of being rewarding, results from their common property of activating neurochemically specific pathways. Natural stimuli accomplish this result indirectly through their sensory properties and incentive learning while drugs stimulate by a direct central action the critical reward pathways. Many drugs of abuse mimic the incentive properties of natural stimuli and their ability to stimulate mesolimbic dopamine pathways (Fig. 1). Both natural rewards and drugs of abuse, including amphetamine, cocaine and other psychostimulants, preferentially stimulate dopamine transmission in the mesolimbic nucleus accumbens compared with the dorsal caudate, an area related to the extrapyramidal motor system. Although many drugs of abuse mimic the incentive aspect of natural reward, this is probably not an absolute prerequisite for conferring to a drug some abuse liability. It might be predicted that certain drugs might be abused as a result of their action at sites located beyond dopamine or by mimicking other aspects of naturally rewarding stimuli such as the 'functional' (or trophotropic). This might be the case with opiates (which also mimic the 'incentive' aspect) and of benzodiazepines, as a result of activation of the central opioid reward system and of the central gamma-aminobutyric acid (GABA)-benzodiazepine system respectively. The hypothesis appears to have heuristic value as it predicts that biochemical mechanisms important for the rewarding properties of drugs of abuse are expected to play a role also in natural reward. One test of this hypothesis is offered by the observation that the 5-hydroxytryptamine (5-HT) system, through 5-HT3 receptors, and the central opioid system, through delta-opioid receptors, can contribute to the mechanism of the dopamine-activating properties of certain drugs of abuse. On this basis it would be predicted that drugs acting on 5-HT3 and on delta-opioid receptors would interfere with or mimic certain aspects of natural rewarding stimuli.