Sickle cell disease is a chronic and life-limiting disorder. Approximately 100,000 Americans are affected with sickle cell disease with most being African Americans. Newborn screening for sickle cell is available in the United States, leading to early detection and management of the disease beginning in infancy. According to the 2014 National Heart, Lung, and Blood Institute sickle cell disease guidelines, supportive care has been primary management of sickle cell disease, with hydroxyurea being the only FDA-approved, disease-modifying pharmacotherapy available and allogeneic hematopoietic stem cell transplant the only cure. Since 2017, three new disease-modifying therapies have been approved by the FDA: L-glutamine, crizanlizumab, and voxelotor. This review will discuss pertinent trials, dosing, interactions, side effects, access, cost, and their role in sickle cell management.