Cancer gene therapy is the most promising and active field in gene therapy treatment. Although previous experimental and clinical trials have brought forward some exciting cases, in general, the clinical benefits have been limited. A major difference between virus-mediated gene therapy and other therapies is the poor physical diffusibility of viral vectors, which is also one of the major obstacles in cancer gene therapy. As safety is a prerequisite to enhanced viral dissemination, tumor-specific targeting becomes crucial. The present review focuses on questions related to efficient viral dissemination in tumor masses and how to sustain a high level of oncolytic virus targeting of tumor cells only. We will first consider two common reasons for limited virus spread in tumor masses and then discuss strategies for improving the tumor-specific oncolysis of currently used viral vectors and to comment on their advantages and potential problems.