Immunosuppressive therapy for acquired severe aplastic anemia improves pancytopenia but has a significant risk of relapse (40%) and clonal evolution to myeloid neoplasms (15%), especially in patients older than 40. Yet, current guidelines for newly diagnosed severe aplastic anemia patients over the age of 40 recommend immunosuppressive therapy instead of curative allogeneic stem cell transplantation. Upfront allogeneic stem cell transplants are restricted to the rare patient who is not only young but also has a matched sibling donor. This article will discuss practice-changing data on the recent advances in upfront alternative donor hematopoietic cell transplants that could rewrite current treatment algorithms.