The concept of using viruses as oncolytic agents is not a new one. In an effort to improve the applicability of viral anti-cancer agents various non-human viruses are being evaluated preclinically and clinically. The application of replication- competent non-human viruses poses new potential hazards, i.e. those associated with the possible adaptation of the therapeutic viruses to the human hosts. Therefore it is essential to weigh the potential benefits for the patients against the risk for the patients, their close contacts, and the greater public. Many aspects of such assessment parallel with the risks and dilemmas associated with the use of live porcine cells, tissues and organs in a clinical xenotransplantation setting. In this review we will summarize the potential biological hazards and list the points that need to be considered in a formal biosafety risk evaluation. The risk evaluation should include the possible environmental aspects of the non-human viruses used, also in case the non-human viruses are not formally designated as genetically modified organisms.