This review focuses on modeling methodologies of the gastrointestinal tract during digestion that have adopted a systems-view approach and, more particularly, on physiologically based compartmental models of food digestion and host–diet–microbiota interactions. This type of modeling appears very promising for integrating the complex stream of mechanisms that must be considered and retrieving a full picture of the digestion process from mouth to colon. We may expect these approaches to become more and more accurate in the future and to serve as a useful means of understanding the physicochemical processes occurring in the gastrointestinal tract, interpreting postprandial in vivo data, making relevant predictions, and designing healthier foods. This review intends to provide a scientific and historical background of this field of research, before discussing the future challenges and potential benefits of the establishment of such a model to study and predict food digestion and absorption in humans. Expected final online publication date for the Annual Review of Food Science and Technology, Volume 12 is March 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.