We have recently validated a new emerging technology based on integration-defective lentiviral vectors showing long-term gene expression while minimizing the risk of insertional oncogenesis. We also validated hyperactive transposons obtained by in vitro Darwinian evolution and selection for stable gene transfer into CD34+ HSC. Most importantly, there was no biased integration into genes when these hyperactive transposons were used which should reduce the risk of insertional oncogenesis. We will continue to explore the use of this transposon technology in disease models including cancer and will further refine the targeting specificity by transposase engineering. In addition, we are assessing the efficiency and safety of meganuclease-mediated gene targeting to specifically integrate the therapeutic transgenes into “genomic safe harbours” of CD34+ HSC.