Despite years of intense research efforts, the treatment and prevention of brain injury with N-methyl-D-aspartate (NMDA) antagonists remains a medical challenge. Numerous clinical trials seeking chemical neuroprotection with prolonged blockade of NMDA receptors (NMDAR) in the setting of cardiac surgery, head trauma, brain ischaemia, subarachnoid haemorrhage, and other acute brain insults failed to show improved patient outcome [1]–[3]. In view of this experience and a more comprehensive understanding of recent pathophysiological findings, two fundamental questions must therefore be raised: Is a treatment strategy of profound NMDAR blockade for neuroprotection still valid in acute brain insults? And, if the principle of reducing unbalanced NMDAR overactivation in order to achieve neuroprotection is applicable, what do improved therapeutic approaches to treating brain injury with NMDAR antagonists look like?