This chapter provides an overview of the toxicokinetics of orally absorbed xenobiotics. This includes a description of the basic anatomy and physiology of the digestive tract most relevant to the absorption process. In addition, differences in anatomy and physiology between humans and animals that may impact interpretation and extrapolation of animal toxicokinetic data are discussed. Mechanisms of oral absorption are described at both the molecular and mathematical levels, including transporters, and the basic concepts of bioavailability and first pass metabolism are introduced. Host and environmental factors that may impact absorption are described, including dose and dose-rate effects. In addition, the nature of metabolism in gastrointestinal tract, in both gastrointestinal tissue and by the gastrointestinal microflora, is characterized and its impact on absorption is discussed.