The gold standard for nutrition studies is clinical trials but they are expensive and variable, and do not always provide the mechanistic information required, hence the increased use of in vitro and increasingly in silico simulations of digestion. In this review, we give examples of the main simulations being used to model upper gastrointestinal tract digestion. This review ranges from the selection of enzymes to the interpretation of results from static models to fully dynamic models. We describe the modifications made to accommodate different demographic groups (infants, the elderly, etc.). We list examples of the application of the different models as well as giving the advantages and disadvantages. A model is only useful if it predicts or aids the understanding of physiological behaviour. Thus, the final section of the review makes a comparison of results obtained from experiments undertaken using in vitro simulations with those obtained in vivo. This comparison will help the reader understand the appropriateness of each model for the type of measurement to be undertaken. In particular, human studies tend to measure bioactive concentrations in blood and not in the gastrointestinal tract whereas in vitro studies often only produce data on release of nutrients into the gut lumen. This is the difficulty of comparing bioaccessibility as generated in vitro with bioavailability as generated in vivo. It is apparent that the models being used are increasingly being validated with in vivo data and this bodes well for the future.