Mice implanted with morphine pellets demonstrated a 30-fold increase in tolerance to subcutaneously administered morphine but showed no cross-tolerance to subcutaneously administered heroin. When given morphine intracerebroventricularly, the mice showed no tolerance to morphine or cross-tolerance to heroin. These observations depended on the presence of the morphine pellet. If the pellets were removed prior to determinations of potency, the expected responses--tolerance to morphine and cross-tolerance to heroin--were obtained. The blood-brain barrier may be a prime site for the expression of morphine tolerance in mice.