Sickle Cell Disease (SCD) is a genetic hematologic disorder characterized by sickle-shaped red blood cells (RBC). Sickle cell disease is a debilitating condition affecting nearly 100,000 people in the USA and millions of people in the world, particularly the population of sub-Saharan Africa. Our previous studies indicate that calpains, a family of calcium-dependent cysteine proteases, play an important role in regulating RBC shape and membrane properties. I am investigating the role of calpains in SCD using genetically modified mouse models. These studies may ultimately lead to the development of calpain inhibitors as potential therapeutics for sickle cell disease.