Gene therapy has become a feasible and efficient strategy for the treatment of human genetic diseases. The main principle of a gene therapeutic regimen relies on the delivery of a corrected gene of interest in human cells. In about one fifth of the clinical trials, gamma-retroviral vectors are used as gene-transfer vehicle. However, previous successful gene therapy trials revealed gamma-retroviral vector-mediated severe adverse events: Upregulation of proto-oncogenes led to malignant transformation of the affected cells and tumor progression. These severe adverse events enhanced the development of new 'safer' gamma-retroviral vectors and comprehensive biosafety studies. This review highlights all possible safety and biosafety risks of gamma-retroviral vectors.