Lentiviral gene transfer vectors (LV) have been used in several hundreds of gene therapy clinical trials around the world, to treat rare genetic disorders including primary immune deficiencies (PIDs), cytopenias, hemoglobin disorders or neurodegenerative diseases, and also to engineer T cells for cancer immunotherapy. At this point, it is possible to reflect on the efficay and safety of lentiviral gene therapy and to discuss future directions in the field. At Genethon, we have developed several LV for hematopoeitic stem cell (HSC)-based gene therapy for rare genetic diseases including vector design, preclinical evaluations and large scale manufacturing in GMP.  We have also conducted international phase I/II clinical trials for the treatment of Wiskott Aldrich syndrome (WAS) or X-linked granulomatous disease (X-CGD).  The long-term evaluation of patients treated for Wiskott Aldrich syndrome confirms the persistence in patients’ blood, of polyclonal populations of gene-corrected cells without evidence of clonal dominance. This long-term follow-up also confirms that hematopoietic gene therapy for WAS can provide sustained clinical benefit even though not all biological parameters are fully corrected. From these studies, it is clear that increasing the level of lentiviral gene transfer and the engraftment of high numbers of gene-corrected cells are key points for the success of HSC-based gene therapy. At this stage, improvements in manufacturing and the standardisation of method are needed in the perspective of registration and patient access. The progress achieved with trailblazing gene therapy studies, can make way for new applications of lentiviral vectors.