In January 2001 a Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Consultation Committee on Allergenicity of Foods Derived from Biotechnology published a report outlining in detail an approach for assessing the allergenic potential of novel proteins. One component of this decision tree is a determination of whether the protein of interest is resistant to proteolytic digestion. Although these in vitro methodologies have been useful, the correlation between resistance to proteolysis and allergenic activity is not absolute. Two views and highlights of supporting research regarding the relationship of resistance to digestion and allergenicity are presented in this article.