Potential safety issues have been raised with the development and release of virus-resistant transgenic plants. This review focuses on safety assessment with a special emphasis on crops that have been commercialized or extensively tested in the field such as squash, papaya, plum, grape, and sugar beet. We discuss topics commonly perceived to be of concern to the environment and to human health-heteroencapsidation, recombination, synergism, gene flow, impact on nontarget organisms, and food safety in terms of allergenicity. The wealth of field observations and experimental data is critically evaluated to draw inferences on the most relevant issues. We also express inside views on the safety and benefits of virus-resistant transgenic plants, and recommend realistic risk assessment approaches to assist their timely deregulation and release.