Adenosine (ADA)-deficient SCID is a primary immunodeficiency characterized by an altered purine metabolism leading to impaired immune responses, susceptibility to severe infections and organ alterations. Gene transfer into hematopoietic stem cells by means of retroviral vectors is an effective treatment for the disease. Our studies are at aimed at investigating the molecular and cellular mechanisms linking the purine metabolism disorder to the immune and non immune alterations of the disease. Studies on vector integrations are providing crucial information on vector biology, the dynamics of genetically modified cells, and the safety of gene therapy. In addition, we are developing new therapeutic strategies based on the use of lentiviral vectors. These studies will contribute to improve current gene therapy approaches and advance patients’ care.