Aplastic anemia is defined as the inability of hematopoietic stem cells to produce mature blood cells, causing pancytopenia. The etiology of aplastic anemia can include physical or chemical damage from cytotoxic drugs and constitutional genetic or “inherited” defects. However, most cases are due to immune-mediated destruction of hematopoietic stem cells and this will be the focus of our chapter. Once considered a fatal disease, optimization of immunosuppressive therapy (IST) and advances in allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been transformative in improving survival rates to over 90% in certain populations. Disease relapse and/or clonal evolution to malignancy after IST has led to the study of new IST agents, thrombopoietin agonists, and expansion of the donor pool for allo-HSCT to improve outcomes and overall survival. Paroxysmal nocturnal hemoglobinuria (PNH) is a clinical syndrome of intravascular hemolysis, thrombosis, and bone marrow failure. It is closely related to immune aplastic anemia; PNH clones are detected in 25–35% of patients with aplastic anemia. Clonal expansion of paroxysmal nocturnal hemoglobinuria (PNH) cells due to an acquired mutation in the PIGA gene is thought to occur as an escape mechanism to immune-mediated hematopoietic stem cell destruction in aplastic anemia. PNH cells are vulnerable to destruction by the complement system, leading to chronic hemolysis and risk for thromboembolism, pulmonary hypertension, and kidney disease. To date, C5 inhibitors that suppress intravascular hemolysis have been the mainstay of PNH treatment. Novel C3 inhibitors show promise in their ability to mediate both intra- and extra- vascular hemolysis and reduce the transfusion burden. Unfortunately, patients with immune-mediated aplastic anemia treated with IST and/or PNH patients treated with C3 or C5 inhibitors remain at risk of malignant transformation to myelodysplastic syndrome and acute myeloid leukemia.