Cocaine is a widely abused psychostimulant. Its direct actions include inhibition of dopamine, serotonin, and norepinephrine reuptake into presynaptic nerve terminals, thereby potentiating the actions of these transmitters in the synapse. A variety of studies have demonstrated that cocaine can also have profound effects on the endogenous opioid system. Compelling evidence points to the importance of mu opioid receptors in human cocaine addiction and craving. Animal studies support these findings and demonstrate that chronic cocaine administration can result in alterations in opioid receptor expression and function as measured by changes in critical signal transduction pathways. This chapter reviews studies on the regulation of opioid receptors as the result of exposure to cocaine.