Increasing blood and plasma viscosity is generally associated with pathological conditions, and increased cardiovascular risk, a perception based in part on studies where blood viscosity is increased to extreme values attained by hemoconcentration. Present studies, supported by epidemiological studies in humans, show that moderate increases in Hct improve cardiovascular function and vice versa. This result is due to the nonlinear regulation of peripheral vascular resistance arising from the increased production of nitric oxide following the increase of shear stress on the vascular wall due to increasing blood viscosity. Similar effects are found in when plasma viscosity is increased in the extremely hemodiluted circulation. In both cases there is an effect at the arteriolar/capillary level, leading to a condition of improved microvascular function and supra perfusion that facilitates clearance of metabolic waste products, while maintaining oxygen delivery. Application of these findings to the design of viscogenic plasma expanders suggests a new approach for the treatment of hemorrhage that in part replaces the use of blood transfusions, making it feasible to lower the transfusion trigger to levels below than normally considered safe.