Ingestion of oral dosage forms with food can drastically change drug pharmacokinetic parameters to consumption in fasted state. Accurate prediction of food effect (FE) is an important focus during drug development, as well as a requirement for drug approval by the Food and Drug Administration. FE can significantly restrict the clinical usefulness of drugs and is a principal parameter that must be considered early in drug development. Several approaches are available to predict FE in the human, including cell culture models, a variety of small and large animal models, and, more recently, physiologically based pharmacokinetic computerized models that incorporate biorelevant drug physicochemical properties. Each has its own advantages and disadvantages. While many methods are available to study FE, not all of these methods are applicable, efficient, consistent, financially feasible, or reasonable for every drug or drug formulation. Most importantly, different models may offer different applicability in accurately predicting FE in human species. Drug development is a long and often expensive process. Understanding of and access to an appropriate, reproducible, frugal means of FE assessment is vital in the field of drug development in order to ensure the development of a safe and effective drug. The following review delineates the advantages and disadvantages of a variety of preclinical FE study methods. While no single approach is good enough to give completely reliable predictions, a combination of in vitro, in vivo, and in silico approach may be advantageous to predict FE.