Since the first discussions on strategies to assess the food safety of genetically modified (GM) crop plants, assessment of GM plants and derived tissues has been based on comparisons with their traditionally bred counterparts. This was termed the Principle of Substantial Equivalence. However, implementation of the principle led to controversy and hampered the precision of the actual safety assessment. Here, we propose the principle be rephrased into the Comparative Safety Assessment strategy. This describes the analytical nature of the first step of the entire (GM) food safety assessment in combination with consecutive toxicological and nutritional evaluations. Further development of advanced analytical methods will help to improve the efficacy of assessment strategies.