Blood rheology plays a key role in hemodynamics and has a major impact on blood flow in both the microcirculation and macrocirculation. The best known blood rheological parameter is blood viscosity. However, most of the handbooks in cardiovascular physiology and medicine consider that blood viscosity is rather stable from one person to another, does not change over time and is around 3.5–5.5 cP, suggesting that its impact on vascular resistance is rather limited. However, blood exhibits a shear thinning behavior, meaning that its viscosity can change across the vascular system. Blood viscosity is highly variable from one subject to another and can reflect and contribute to various diseases. Hematocrit and plasma viscosity influence blood viscosity at both low and high shear rates. The shear thinning property of blood is mainly attributed to red blood cell (RBC) aggregation and deformability properties. RBC aggregation occurs at low shear rates, increases blood viscosity and depends on both cellular (RBC aggregability) and plasma factors. Any decrease in RBC deformability may impact blood viscosity and blood flow into the microcirculation. Indeed, any changes in one or several of these parameters may affect blood viscosity differently. Sickle cell disease is the prototype of an hemorheological disease, mainly marked by the presence of very rigid RBCs. Blood rheological alterations have been found to be associated with various clinical complications in sickle cell disease patients and several drugs are targeting some of these abnormalities to improve the clinical condition of the patients.