The compositional equivalency between genetically modified (GM) crops and nontransgenic comparators has been a fundamental component of human health safety assessment for 20 years. During this time, a large amount of information has been amassed on the compositional changes that accompany both the transgenesis process and traditional breeding methods; additionally, the genetic mechanisms behind these changes have been elucidated. After two decades, scientists are encouraged to objectively assess this body of literature and determine if sufficient scientific uncertainty still exists to continue the general requirement for these studies to support the safety assessment of transgenic crops. It is concluded that suspect unintended compositional effects that could be caused by genetic modification have not materialized on the basis of this substantial literature. Hence, compositional equivalence studies uniquely required for GM crops may no longer be justified on the basis of scientific uncertainty.