Hereditary disorders that trace their origin to the hematopoietic stem cell have been targeted for allogeneic therapy and were among the first human diseases cured by successful hematopoietic cell transplantation (HCT). More recently, the possibility of treating nonhematopoietic hereditary disorders in which engraftment of hematopoietic cells might ameliorate tissue damage in target organs has also been investigated with encouraging results. As in the malignant hematological disorders, transplantation results have improved over the past 3 decades as a consequence of more refined donor selection and patient risk stratification with modifications to the conditioning regimen. The application of these principles is described in this update about HCT for hereditary marrow failure syndromes and hemoglobin disorders. In addition, a novel indication of HCT for epidermolysis bullosa is presented. Together, these representative disorders illustrate the potential for an expanding role of HCT for nonmalignant disorders.