Morphine and other opioids are used and abused for their analgesic and rewarding properties. Tolerance to these effects develops over hours/days to weeks, as can physical and psychological dependence. Despite much investigation, the precise cellular mechanisms underlying opioid tolerance and dependence remain elusive. Recent studies examining mu-opioid receptor desensitization and trafficking have revealed several potential mechanisms for acute receptor regulation. Other studies have reported changes in many other proteins that develop during chronic opioid treatment or withdrawal and such changes may be partly responsible for the cellular and synaptic adaptations to prolonged opioid exposure. While these studies have added to our knowledge of the cellular processes participating in opioid tolerance and dependence, the challenge remains to integrate these observations into a coherent explanation of the complex changes observed in whole animals chronically exposed to opioids.