Typical cases of severe combined immunodeficiency present at infancy (most frequently at 6 months of age) with repeated opportunistic infections; failure to thrive; and scarcity of lymphoid tissues, including undetectable lymph nodes and a small dysplastic thymus. Patients with profound T-cell dysfunction (PTD)/combined immunodeficiency (CID) have moderate to large numbers of circulating autologous lymphocytes with variable residual function. These cells may interfere with proper engraftment and may complicate the procedure of HSCT, hence the need for conditioning. There is no immediate explanation for the excellent outcome of hematopoietic stem cell transplantation (HSCT) for PTD/CID. Historically, protocols for mismatched related donor HSCT did not include conditioning regimens, which could jeopardize engraftment. Careful studies on the role of conditioning, especially myeloablative conditioning, should be conducted in the future. It is possible that in some genotypes, related identical donor can be accepted by the recipient with little or no conditioning. Until such studies become instructive, the protocols in current use seem to provide excellent, although not perfect, outcome in patients with PTD/CID.