Rigidity, hyperthermia, and elevated levels of creatine phosphokinase are the essential features of "neuroleptic malignant syndrome" (NMS), a clinical condition caused either by pharmacological treatment with dopamine receptor antagonists or by the withdrawal of dopamine receptor agonists. An acute dopaminergic transmission block in the basal ganglia and the hypothalamus is thought to be the pathophysiological mechanism of NMS. NMS, the "malignant dopamine depletion syndrome", and the akinetic Parkinsonian crisis may be considered identical conditions with regard to their presumptive pathogenesis. Centrally acting dopamine receptor agonists and the peripheral calcium antagonist, dantrolene, are the most common adjunctive pharmacological approaches to NMS, although their efficacy has been questioned. The motor symptoms and the autonomic nervous system disturbances of NMS may be related to a relative glutamatergic transmission excess, as a consequence of a dopaminergic block. Therefore, we recommend the application of N-methyl-D-aspartate (NMDA) receptor antagonists such as amantadine or memantine for the management of NMS. These drugs counteract excitatory amino acid neurotransmission and exhibit hypothermic and central muscle relaxant properties. However, identification and reversal of the causative event, such as neuroleptic drug therapy or change of anti-parkinsonian medication, remain the cornerstones for reducing the incidence and mortality of NMS.