Studies concerning drugs of abuse have made major contributions in defining the circuitry, as well as cellular and molecular substrates that underlie certain behaviors. Opiate drugs for example, have revealed important insights concerning pain perception and reward. Up to the late 1960s, opiate drugs were suspected to work by mysteriously perturbing lipid membrane structure. We now know the following: the sequence and neuroanatomy of the G-protein coupled receptors that mediate opiate effects; that many proteins interact with opioid receptors such as G-protein sub-unit combinations, G-protein receptor kinases, arrestins and calmodulin; that many signaling molecules are modulated by opioid receptors, including ion channels, kinase cascades and adenyl cyclase. More than 20 different peptides, excised from three precursor proteins by specific proteases, have been shown to be endogenous ligands for opioid receptors. Revealing the molecules of the endogenous opioid system has inspired efforts for developing new opioid analgesics with the hope of minimizing abuse potential. This article will detail the current rationale for searching for less-addictive opiate analgesics and speculate on the future of drug abuse research in furthering our understanding of neural plasticity and the underpinnings of addictive behavior.