The recent incidents of leukemia development in X-SCID patients after a successful treatment of the disease with retroviral gene therapy raised concerns regarding the safety of the use of retroviral vectors in clinical gene therapy. In this review, we have tried to re-evaluate the safety issues related to the use of retroviral vectors in human clinical trials and to suggest possible appropriate solutions to the issues. As revealed by the X-SCID incident, oncogenesis caused by retroviral insertional activation of host genes is one of the most prominent risks. An ultimate solution to this problem will be in re-engineering retroviral vectors so that the retroviral insertion takes place only at the desired specific sites of the host cell chromosome. This is, however, a technically demanding tasks, and it will take years to develop retroviral vectors with targeted insertion capability. In the mean time, the use of chromatin insulators can reduce chances for retrovirus-mediated oncogenesis by inhibiting non-specific activation of nearby cellular proto-oncogenes. Co-transduction of a suicidal gene under the control of an inducible promoter could also be one of the important safety features, since destruction of transduced cells can be triggered if abnormal growth is observed. Additionally, conditional expression of the transgene only in appropriate target cells via the combination of targeted transduction, cell type-specific expression, and targeted local administration will increase the overall safety of the retroviral systems. Finally, splitting of the viral genome, use of self-inactivating (SIN) retroviral vectors, or complete removal of the coding sequences for gag, pol, and env genes is desirable to virtually eliminate the possibility of generation of replication competent retroviruses (RCR).