More than 20,000 patients have participated in clinical trials of more than 100 neuroprotective therapies, but no study has provided convincing evidence of benefit. Several improvements to the rigor of preclinical agent qualification have been identified to increase the likelihood of success in human clinical trials: stringent randomization and blinding techniques to mitigate observer bias; assessment in in time periods achievable in the clinical setting; testing in older animals with comorbidities; and robust and reproducible benefit magnitudes. Human clinical trials should start agents hyperacutely, in the first minutes and hours after onset, when treatment effect would be maximal; target enrolment of patients likely to have transient rather than permanent ischaemic exposure; and use factorial and platform trial designs that would permit efficient testing of combinations of agents able to block multiple ischaemic injury-mediating pathways concurrently, including both anti-necrotic and anti-apoptotic interventions. For agents that allow cells to endure ischaemic stress, human trial delivery approaches include: prehospital initiation; initiation immediately upon brain imaging in patients destined for endovascular intervention; and initiation at outside hospitals in patients undergoing transfer to a neurothrombectomy center. For agents that mitigate reperfusion injury, treatment start before or concurrent with reperfusion, including intra-arterial administration via catheter immediately after endovascular thrombectomy, should be pursued.