Since the first cord blood transplantation (CBT), many indications have been proven for this stem cell therapy. Besides the standard hematological indications, such as leukemia, lymphomas, and aplastic anemia, CBT has also been a proven curative therapy for non-hematological indications such as Krabbe’s disease, and osteopetrosis. As transplant-related mortality (TRM), overall survival (OS) and disease-free survival (DFS) for CBT continue to improve with larger inventories, double CBT, higher cell dose CB products, optimal conditioning, GvHD, HLA matching, and infection prophylaxis and treatment, the utility of this stem cell source will expand to certain indications which in the past, rarely used CBT. For patients and physicians to accept CBT for indications such as thalassemia, autoimmune diseases or HIV, the benefit-risk ratio has to be significantly improved so that patients will take a chance on a risky procedure in order to improve their lifespan or quality of life. We review here some of the efforts to improve clinical outcome of CBT for thalassemia through increasing cell dosage using a combination strategy – (1) Chow’s MaxCell second and third generation technologies that maximize CB cell dosage, (2) double CBT, (3) no-wash thaw direct infusion advocated by Chow et al., and (4) optimal product selection.