Multi-modality therapy for acute ischaemic stroke is an emerging concept stimulated by the existing vacuum in stroke treatment and an increasing understanding of the ischaemic cascade. Experimental studies have shown that infarct size can be reduced more by combinations of reperfusion and neuroprotective strategies than by either one alone. An optimal combination regimen remains to be determined, but will probably target several sequential events occurring after ischaemia. Many logistic hurdles must be overcome before multimodality therapy can be properly tested in clinical trials. This will require a combination of pragmatism, adherence to scientific principles, and international cooperation among clinic investigators.