The complexity of food organism interactions necessitates the use of model organisms to understand physiological and pathological processes. In nutrition research, model organisms were initially used to understand how macro and micronutrients are handled in the organism. Currently, in nutritional systems biology, models of increasing complexity are needed in order to determine the global organisation of a biological system and the interaction with food and food components. Originally driven by genetics, certain model organisms have become most prominent. Model organisms are more accessible systems than human beings and include bacteria, yeast, flies, worms, and mammals such as mice. Here, the origin and the reasons to become the most prominent models are presented. Moreover, their applicability in molecular nutrition research is illustrated with selected examples.