Severe combined immunodeficiencies are usually fatal diseases unless affected children are admitted to protective isolation unit or unless the underlying immunological defect is treated by transplanting bone marrow from an healthy donor. The patients present, with early onset, life-threatening infections from fungal, viral or bacterial agents. Since only a minority of patients has an HLA-identical donor, recently other strategies have been devised including bone marrow transplantation from donors other than HLA-identical within the family or from HLA-non identical family members or from HLA-matched unrelated donors included in the International Bone Marrow Volunteers' Registry. In these cases, in order to realize this approach the "purging" of T-cells of the HLA-non identical donor bone marrow is necessary. Overall survival after HLA-identical BMT is 76%, when all BMT of the European multicenter analysis are considered, while in BMT from non-identical donors is 56%. Recently particular cases of SCID caused by enzyme deficiency, such as adenosine-deaminase (ADA), have been treated by molecular therapy with administration of polyethylene glycol (PEG) conjugated ADA: PEG protects from degradation and inhibits clearance of the enzyme. This approach, already realized in 15 children, allows reconstitution of cellular and humoral immunity, as demonstrated by one case treated by our group.