The results of large-scale clinical trials of hemodilution therapy and vasodilators for acute stroke have been disappointing. However, interventions involving the manipulation of whole blood viscosity, blood oxygen-carrying capacity, cardiac output, and the resistance properties of cerebral vessels are viable therapeutic modalities currently being investigated. The central aim of all of these therapies is the timely improvement of perfusion and substrate delivery to ischemic brain regions. Better understanding of cerebrovascular flow regulation and the physiology of microvessels may give rise to more effective therapies. In the past, overemphasis on hematocrit reduction and cerebral vasodilators has obscured the potential risks of reducing blood oxygen content and vascular resistance during acute stroke and the importance of optimizing oxygen delivery by other means, in particular by cardiac output augmentation and manipulation of plasma properties. A broader approach to therapeutic strategies for acute stroke includes not only increasing cerebral blood flow, but also interventions that will create favorable changes in the humoral microenvironment and promote overall substrate delivery to the brain.