Allogeneic hematopoietic cell transplantation (HCT) can be curative for a variety of non-malignant diseases (NMDs) as well as hematological malignancies. However, there are several fundamental differences between HCT for NMDs and hematological malignancies, which may necessitate the use of alternative HCT strategies. For example, these diseases differ in the intensity of conditioning regimen sufficient to improve disease. In addition, patients with NMDs are at higher risk of graft failure or mixed chimerism following HCT, and gain no or little survival benefit from graft-versus-host disease. Because more than 80% of patients with NMDs become long-term survivors, greater attention has been paid to late adverse effects and decreased of quality of life after HCT. This review addresses several unresolved issues in allogeneic HCT for patients with NMDs, such as (1) stem cell source, (2) conditioning regimen, (3) use of serotherapy or low-dose irradiation, and (4) therapeutic intervention for mixed chimerism. Resolving these issues may improve transplant outcomes in patients with NMDs.© 2022. Japanese Society of Hematology.