Despite the advances in gene therapy at the clinical and pre-clinical front, the field has also faced some setbacks. Thes was comounded by safety concerns related to the risk of insertional oncogenesis associated with the use of γ-retroviral vectors due to their biased integration into genes and the intrinsic genotoxic effects of the viral promoter/enhancer sequences. Consequently, controlling the fate of the transgenes became one of the priorities in the field. Fortunately, these hurdles are not insurmountable. Indeed, gene transfer technologies are improving rapidly and we and others are developing vectors which have fewer side-effects without compromising efficacy. To further minimize the risks of insertional oncogenesis, we are currently exploring the use of (i) integration-defective lentiviral vectors, (ii) hyperactive transposons and (iii) meganuclease-mediated gene targeting. At the same token, we are exploring integrating vector systems to identify new mechanisms that influence oncogenicity.