Tolerance is a complex phenomenon with important therapeutic implications. Understanding of its clinical aspects has been hampered by inadequate communication between clinicians, who have acquired striking observations relevant to the stability of the dose-response relationship in patients with pain, and investigators who have extensively studied animal models or drug effects in former addicts. In the clinical setting, it is now clear that the loss of analgesic effects over time has a differential diagnosis, only one component of which is tolerance. Evidence from a variety of sources suggests that true pharmacological tolerance to the analgesic effects of opioids is an uncommon cause for the need to escalate the opioid dose to maintain analgesic effects. Tolerance to non-analgesic effects appears to occur more reliably, but this phenomenon, too, is neither uniform nor simple. Some patients who appear to have developed tolerance to these adverse effects demonstrate a remarkable lack of tolerance when the pain is eliminated by some unrelated mechanism. The disparity between these clinical observations and the experimental literature on tolerance suggests that mechanisms related to the pain itself may have an important modulating effect on these phenomena. From the clinical perspective, the disparity emphasizes the need to avoid generalization from the laboratory to the clinic without adequate confirmation.