Although retroviral vectors based upon the murine leukemia virus have good safety records from clinical trials, attention to safety issues is crucial for the advancement of retroviral gene therapy. Key issues are to reduce uncontrolled transfer of viral or non-viral genetic information and to prevent the formation of replicating retroviruses. Safety features are also being incorporated into the novel attenuated lentiviral vectors that open new prospects for gene delivery. Here, we highlight features developed to restrict the transfer of viral genes, immobilize transfer vectors in target cells, or control interactions with other retroviruses in producer or target cells, as well as new developments in tissue-targeted and regulated vectors.