Gene therapy using genome-integrating vectors carrying corrective genes offers great potential for the treatment of diseases with an association to genetic defects. Retroviral vectors are still by far the most efficient tools for gene therapy. However, the induction of T-cell lymphoproliferative disease in four patients with X-linked SCID undergoing retroviral gene therapy demonstrated the requirement for an improved knowledge of the genetic and molecular effects of retroviruses on the host. This review investigates developments on the molecular mechanisms of oncogenesis by retroviruses and examines how safer vectors could be designed. The target sites of integration, the most crucial factor associated with oncogenicity, are distinct for different retroviruses and should be considered when choosing vectors. Furthermore, insertional activation of non-coding sequences, such as microRNAs, in addition to insertional effects on protein-coding genes, should be examined when considering the risks of retroviral therapy.