This chapter summarizes several experiments intended to provide some insight into the mechanisms by which hemodilution alters cerebral blood flow (CBF) in the normal brain. The results demonstrated that the expected increase in CBF has been accompanied by an increase in CBV indicating the occurrence of at least some active cerebrovasodilation. Tissue hematocrit has also been lower than arterial hematocrit. More importantly, tissue hematocrit decreased more rapidly during hemodilution than did arterial hematocrit. There are no differences in the flow patterns seen in the hemisphere contralateral to the lesion. However, a very different pattern has been seen for cortical CBF from anterior and posterior portions of the lesioned hemisphere, with a marked attenuation of the CBF response to hemodilution seen in lesioned animals. These results again support the concept that the CBF responses to hemodilution are active and can be abolished over a wide area by a small focal lesion. Two groups have directly compared the CBF effects of hypoxia and hemodilution. Both reported that reductions in CaO2 produced by either intervention resulted in similar CBF increases, suggesting that viscosity played little role. It has been suggest that nitric oxide (NO) may be playing a different role in hypoxic versus diluted animals. It is also speculated that this may be related to induce spreading depression, with consequent alterations in the function of N-methyl-D-aspartate (NMDA) receptor and perhaps NO production.