Drugs are absorbed after oral administration as a consequence of a complex array of interactions between the drug, its formulation, and the gastrointestinal (GI) tract. The presence of food within the GI tract impacts significantly on transit profiles, pH, and its solubilization capacity. Consequently, food would be expected to affect the absorption of co-administered drugs when their physicochemical properties are sensitive to these changes. The physicochemical basis by which ingested food/lipids induce changes in the GI tract and influence drug absorption are reviewed. The process of lipid digestion is briefly reviewed and considered in the context of the absorption of poorly water-soluble drugs. The effect of food on GI pH is reviewed in terms of location (stomach, upper and lower small intestine) and the temporal relationship between pH and drug absorption. Case studies are presented in which postprandial changes in bioavailability are rationalized in terms of the sensitivity of the physicochemical properties of the administered drug to the altered GI environment.