Over the last several years, significant progress has been made in our understanding of interactions between the N-methyl-D-aspartate (NMDA) and opioid receptors. Such interactions have been demonstrated at two distinct sites: (1) modulation of NMDA receptor-mediated electrophysiological events by opioids; and (2) intracellular events involving interactions between NMDA and opioid receptors. Furthermore, a considerable number of studies have shown the involvement of such interactions in neural mechanisms of nociceptive transmission, antinociception in acute and chronic pain states, opioid tolerance/dependence, and neuroplasticity. Importantly, emerging evidence indicates that activation of NMDA receptors may differentially modulate functions mediated by distinct opioid receptor subtypes, namely mu, delta, and kappa receptors. These studies have greatly enriched our knowledge regarding both NMDA and opioid receptor systems and have shed light on neurobiology of both acute and chronic pain. The advancement of such knowledge also promotes new strategies for better clinical management of pain patients.