Substantial equivalence (SE) was first described in 1993 and implemented in 1998 by the OECD, and it was endorsed in 1996 by the FAO. It was introduced to provide a “dynamic, analytical exercise” in the safety assessment of novel foods derived from modern biotechnology, i.e. mainly genetically modified (GM) food, by means of comparison with traditional food. Beyond its specific scope of applications, SE appears very useful in revealing the way we perceive food in general. Although SE is bound to a number of limitations, some of which are described in this paper, its main virtue is to give us the opportunity to broaden our comprehension of food, in terms of quality and worth.