Oral drug administration is the most convenient method to administer drugs, particularly in the treatment of chronic diseases. This preference is generally the case, even when the site of drug action is beyond the gastrointestinal tract (GI), requiring the drug to be systemically available. For systemic drug availability, drug dosing via the oral route requires the drug to exhibit sufficient gastrointestinal absorption. Two components of drug absorption from solid oral-dosage forms (e.g., tablets, capsules) are: (1) drug dissolution from the dosage form, which results in the drug being in solution within the gut lumen, and (2) drug permeation across the GI wall. In this chapter, elements of GI drug permeability are discussed, with special emphasis on the enterocyte and the in vitro Caco-2 cell model. Included is a discussion of the lipid plasma membrane, in vitro drug permeability and its relation to in vivo permeability, and a discussion of future research directions.