Peri-operative brain injury continues to occur in cardiac surgery despite a significant effort in preventative research spanning 50 years. There has been much interest in pharmacologic neuro-protection. Six drugs, thiopentone, prostacyclin, nimodipine, remacemide, lignocaine, and Glypromate, have been the subject of one or more randomized controlled trials (RCTs). Only the results for Glypromate are unknown at this stage. In all other cases, the studies have been negative, equivocal, or initially positive but followed by negative studies. Lignocaine is arguably the most extensively studied. In vitro and in vivo experiments that proved lignocaine to be neuro-protective were followed by two RCTs that showed reductions in post-operative cognitive deficits. However, two further RCTs have failed to demonstrate benefit. Lignocaine cannot be recommended for neuro-protection in cardiac surgery at this time, but a role in clinical neuro-protection in this or other contexts is not ruled out.