International consensus has been reached on the principles regarding evaluation of the food safety of genetically modified plants (GMPs). The concept of substantial equivalence has been developed as part of a safety evaluation framework, based on the idea that existing foods can serve as a basis for comparing the properties of genetically modified foods with the appropriate counterpart. Application of the concept is not a safety assessment per se, but helps to identify similarities and differences between the existing food and the new product, which are then subject to further toxicological investigation. Substantial equivalence is a starting point in the safety evaluation, rather than an endpoint of the assessment Consensus on practical application of the principle should be further elaborated. Experiences with the safety testing of newly inserted Cry9C or CryIAc proteins and of whole genetically modified foods (GMFs) are reviewed, and limitations of current test methodologies are discussed. The development and validation of new profiling methods such as DNA microarray technology, proteomics, and metabolomics for the identification and characterization of unintended effects, which may occur as a result of the genetic modification, is recommended. The assessment of the allergenicity of newly inserted proteins and of marker genes is discussed. The safety assessment of transgenic plants is a challenging and fascinating intersection of many disciplines of study, such as agronomy, molecular biology and ecology. Assessing the safety of releases is an activity of fundamental importance for the protection of environmental and nontarget insects. it is worthwhile to appreciate the broader background against which safety assessments are being performed.