Chronic pain, particularly neuropathic pain, is notoriously difficult to treat. NMDA receptor antagonists are effective in reducing pain hypersensitivity in animal models and clinical settings but are associated with an unacceptable level of side-effects. Recent studies of the role of a family of synaptic membrane-associated guanylate kinase proteins in chronic pain provide new insights into central mechanisms of chronic pain that could result in new biochemical targets for its treatment.