Recent insights have demonstrated a central role for dopaminergic neurotransmission in modulating pain perception and natural analgesia within supraspinal regions, including the basal ganglia, insula, anterior cingulate cortex, thalamus and periaqueductal gray. In addition, while the participation of serotonin and norepinephrine in spinal descending inhibition of pain is well known, a critical role for dopamine in descending inhibition has also been demonstrated. Decreased levels of dopamine likely contribute to the painful symptoms that frequently occur in Parkinson's disease. Moreover, abnormalities in dopaminergic neurotransmission have been objectively demonstrated in painful clinical conditions, including burning mouth syndrome, fibromyalgia and restless legs syndrome. Evidence from animal models and indirect evidence from pharmaceutical trials also suggest a role for dopamine in chronic regional pain syndrome and painful diabetic neuropathy. Several novel classes of medication with analgesic properties have bearing on dopaminergic activity as evident in the capacity of dopamine antagonists to attenuate their analgesic capacity. An expanded appreciation for the role of dopamine in natural analgesia provides the impetus for further study involving preclinical models and advanced neuroimaging techniques in humans, which may lead to the development of novel therapeutic strategies.