This review highlights the potential benefits and challenges of the application of Hematopoietic Cell Therapy (HCT) to the treatment of three rare genetic conditions affecting immunohematopoiesis early in life: IPEX (Immune dysregulation, Polyendocrinopathy, X-linked), ALPS (Autoimmune Lymphoproliferative s.), and Dyskeratosis Congenita (DC). Each of these conditions can result from several distinct genetic defects with somewhat distinct clinical prognoses. Severe, life-threatening, autoimmune complications are seen with IPEX and ALPS. In the DC disorders, marrow failure is a common abnormality. ALPS and DC are associated with increased risk of hematopoietic malignancy. Early experience with HCT in these disorders predict that most of the life-threatening complications of these conditions are reversible and/or preventable by HCT. In the current era, it is advised that affected patients undergo definitive genetic diagnosis, and be considered for reduced intensity HCT when young and relatively healthy. © 2007 American Society for Blood and Marrow Transplantation.