For red blood cells (RBC) to survive in the harsh hemodynamic environment of the circulation in vivo, they must remain non-adhesive and maintain a set of unique stability. In healthy humans, RBC survive for about 120 days in the circulation, whereas in certain pathological conditions where membrane stability, cellular deformability or adhesiveness are compromised, the lifespan of the RBC can be dramatically reduced or its function severely compromised, often with severe clinical manifestations. Of a number of disorders affecting the mechanical and adhesive properties of human RBC, homozygous sickle cell disease and malaria are arguably the most important and certainly, in the case of malaria, the most studied. In this chapter, we review the structure-function relationships that determine the mechanical and adhesive properties of RBC and describe some techniques and methods, old and new, for quantifying these important rheological properties. In particular, we concentrate on RBC infected with malaria parasites as a specific example of how recent research on this human pathogen has not only advanced our knowledge of this important human disease and opened up new possible avenues for therapy, but has also increased our understanding of RBC structure-function relationships at the molecular level and the mechanisms that regulate and maintain their unique rheological properties.