The Glycemic Index (GI) has been described by an official method ISO (International Organization for Standardization) 26642:2010 for labeling purposes. The development of in vitro methods for GI measurement has faced significant challenges. Mass transfer and reaction engineering theory may assist in providing a quantitative understanding of in vitro starch digestion and glycemic response from an engineering point of view. We suggest that in vitro GI measurements should consider the mouth and the stomach in terms of fluid mechanics, mass transfer, length scale changes, and food-solvent reactions, and might consider a significant role for the intestine as an absorption system for the glucose that is generated before the intestine. Applying mass transfer and reaction engineering theory may be useful to understand quantitative studies of in vitro GI measurements. The relative importance of reactions and mass-transfer has been estimated from literature measurements through estimating the Damköhler numbers (Da), and the values estimated of this dimensionless group (0.04–2.9) suggest that both mass transfer and chemical reaction are important aspects to consider.