In summary, many of our once generally accepted ideas about tolerance and dependence have been revised as the result of neuropharmacological research. Included among these concepts are the following: Although tolerance and dependence are usually linked, they appear to be separable phenomena in some instances. Further exploration into each should be profitable. Although chronic administration of a drug is usually required to produce tolerance and dependence, even a single dose can result in these effects under certain conditions. That fact may provide us with clues as to the neuroadaptive changes occurring during the development of tolerance and dependence. A fruitful line of research emanates from the findings that tolerance may be pharmacokinetic or neuronal and that time of receptor occupancy appears to be a vital factor in neuronal tolerance. It is now known that tolerance does not develop equally to all actions of a drug and reverse tolerance (increased responsiveness) can occur. Further studies along these lines are needed to correct many false assumptions about this issue and to shed new light on the receptors and transmitter systems involved. We now accept the notion that a drug usually exerts effects on more than one receptor type or subtype. Consequently, the actions of drugs on the various receptors and the responses to receptor blockade promise to yield significant new knowledge about the mechanisms involved in tolerance and dependence to a wide variety of drugs. We have become increasingly aware of species differences and genetic determinants of responses to drugs of abuse, after both acute and chronic dosing. Other papers in this volume will focus on this topic.