The bioavailability of food nutrients and microconstituents is recognized as a determinant factor for optimal health status. However, human and animal studies are expensive and limited by the large amount of potential food bioactive compounds. The search for alternatives is very active and raises many questions. On one hand, in vitro digestion systems are good candidates, but to date only bioaccessibility has been correctly assessed. To go further, to what degree should natural processes be reproduced? What techniques can be used to measure the changes in food properties and structures in situ in a noninvasive way? On the other hand, modeling approaches have good potential, but their development is time-consuming. What compromises should be done between food and physiology realism and computational ease? This review addresses these questions by identifying highly resolved analytical methods, detailed computer models and simulations, and the most promising dynamic in vitro systems.