This review focuses on the long-term adaptations opiates and cocaine induce in specific regions of the nervous system that underlie the additive actions of the drugs, and the mechanisms by which such adaptations are achieved. To date, opiate and cocaine regulation of post-receptor, intracellular messenger pathways has shed considerable light on the mechanisms underlying chronic drug action. Of particular interest is the up-regulation of the cyclic AMP pathway observed in the locus coeruleus (LC), a brain region involved in physical opiate addition, in response to chronic opiate administration. Up-regulation of the cyclic AMP pathway has been shown to contribute to the opiate tolerance, dependence, and withdrawal exhibited by these neurons electrophysiologically. A similar up-regulation of the cyclic AMP pathway in response to chronic opiate and chronic cocaine treatments has been observed in the mesolimbic dopamine system, which is implicated in the psychological aspects of drug addiction. Several lines of evidence suggest the possibility that these biochemical adaptations may contribute to opiate and cocaine regulation of this neural pathway. Related studies in inbred rat strains raise the additional possibility that similar adaptations may contribute to individual genetic vulnerability to drug addition. Current studies are aimed at investigating opiate and cocaine regulation of transcription factors in these discrete brain regions to identify the molecular mechanisms involved in drug action. The investigations have focused on the Fos-Jun family of immediate early gene transcription factors, and the CREB family of transcription factors, as possible mediators of the effects of chronic opiate and cocaine exposure on regulation of neuronal gene expression. Ultimately, more direct analyses are needed that make use of methods for detecting changes in target gene expression in vivo. Together, these studies of opiate and cocaine action will help define the precise mechanisms, at the molecular level, by which these drugs of abuse alter the expression of specific genes in particular neuronal cell types and thereby produce physical and psychological aspects of drug addition.