Sickle cell anemia (SCA) is a homozygous recessive genetic disorder affecting nearly 100,000 people in the United States and millions worldwide. A mutation in the β-globin subunit of hemoglobin causes polymerization into rigid fibers after deoxygenation within red blood cells (RBCs), deforming them into a “sickle” shape. Sickled RBCs cause blockage of vessels in postcapillary venules, ischemia, and pain. Accumulation of membrane damage causes hemolysis of the RBCs, reducing the number of circulating RBCs and anemia. Hemolysis also stimulates chronic vascular damage after releasing heme into plasma, increased systemic levels of inflammatory cytokines, and subsequent consequential effects that damage multiple tissues and organ systems. Sickling of RBCs happens under deoxygenated conditions, beginning in the capillaries where gas exchange occurs, and vaso-occlusions form in the postcapillary venules. This makes microcirculation a prime region for studies to understand pathological complications of sickle cell anemia. Though the initiating cause is the mutation in β-globin protein, the resultant pathological processes are numerous. This chapter will discuss underlying mechanisms, describe links between a mutation in red blood cells altering cell behavior in the microcirculation and systemic damage to shortening of life spans for individuals with SCA, and identify targets for treatment and current therapies.