Recent research has demonstrated that N-methyl-D-aspartate (NMDA) receptors, a class of excitatory amino acid receptors, may have an important role in opiate tolerance and physical dependence. Much of the evidence for this has arisen from studies that have examined the effects of NMDA receptor antagonists on these phenomena. This article summarizes research from our laboratory on the effects of NMDA receptor antagonists on opiate tolerance and dependence in rats. Noncompetitive NMDA antagonists, including MK-801, ketamine, phencyclidine, and dextrorphan have been found at low doses to inhibit the development, or acquisition, of opiate tolerance and dependence but not the expression. The results suggest that NMDA receptors have a role in the neural plasticity responsible for tolerance and dependence. Selected theoretical and therapeutic implications of these findings are discussed.