Genetically modified plants with stacked events (stacked GM), the combination of two or more transgenic traits in a plant, have been the most promising transgenic products due to their multiple functions and efficient utilization of resources. However, the potential interactions among multiple transgenes might affect the safety of plants. Therefore, higher standards should be applied to the safety assessment of GM stacked events. Currently, few guidelines have been published by any country or international organizations other than the European Union. The guidance established by the European Union on GM stacked events was applied as a framework for the safety assessment in this article. This system was briefly described in the aspects of choosing reference objects, assessing molecular characteristics, comparative analysis, assessing environmental risks and toxicology/allergenicity and evaluating nutritional effects. The problems worthy of attention were also pointed out and discussed.