Vincristine is one of the most widely used and more effective drugs in paediatric oncology. The dose-limiting toxicity of neuropathy, lack of proven neuroprotective measures and an incomplete understanding of the pharmacokinetics and pharmacogenetics of vincristine have limited its therapeutic potential. Recent advances in the understanding of vincristine pharmacokinetics and pharmacogenetics, and potential methods of preventing neurotoxicity are reviewed which could enable dose escalation and dose individualisation in order to enhance the therapeutic index.