OBJECTIVES: The aim of the research is to present an overview of the current knowledge about the possibilities and challenges of a primary high grade osteosarcoma treatment using gene therapy through recombinant viruses. Hypotheses are: 1. Gene therapy with recombinant viruses represents potential for the treatment of a primary high grade osteosarcoma. 2. The mechanism of virus induced oncolysis differs from the mechanism of antitumor drugs effect on tumor cells, and the effect of antitumor drugs can be increased in combination with virotherapy. 3. The development of virotherapy could improve the outcome of patients with osteosarcoma. MATERIALS AND METHODS: The research gives an overview of the possibilities of oncolytic virotherapy application in achieving a better outcome of treatment and the quality of life for patients with primary high osteosarcoma. Problems with the current treatment of this tumour and the reasons for seeking new ways of treating this type of tumour are presented. Oncolytic mechanisms of different types of viruses on tumour cells and problems that need to be solved in order to make this kind of therapy clinically applicable and successful are described, as well as possible strategies for solving these challenges. RESULTS: The proposed research provides insights into the mechanism of action of recombinant viruses on tumour cells, strategies for overcoming problems in their use in vivo, and potential sites of recombinant virus activity on osteosarcoma tumor cells, which could serve as a source of information to explore new ways of treating osteosarcoma, as well as treating others type of malignant tumours in humans. CONCLUSION: The inability to cure all persons with osteosarcoma with a high degree of malignancy in the past therapeutic protocols, requires the development of new therapeutic approaches in addressing this disease. Preclinical and clinical studies have demonstrated the scientific and clinical validity of the use of oncolytic virotherapy in order to improve outcomes in persons suffering from osteosarcoma with a high degree of malignancy, and that it could be used in combination with other therapeutic modalities. It is therefore justifiable to continue research in order to improve the efficacy and safety of oncolytic virotherapy in persons suffering from osteosarcoma with a high degree of malignancy.