Neuroprotective therapies for acute ischaemic stroke have yet to be realised despite the determined efforts of basic science and clinical investigators. Progressive elucidation of the complex pathophysiology involved in the ischaemic cascade has led to the development of numerous candidate interventions. Preliminary efficacy in animal models has repeatedly resulted in frustration after extensive clinical testing. Failure in the translation of results from animal models to humans implicates potential limitations of the current drug development process. Reflection on prior studies suggests possible flaws at several stages. Incorporation of standardised guidelines for preclinical testing of putative neuroprotective therapies and modification of clinical trial design, methodology and reporting may improve chances for success. The future of neuroprotection for stroke remains bright in spite of previous disappointments.