This chapter presents a variety of illustrative examples which demonstrate toxicity to and the responses of the gastrointestinal (GI) tract to the presence of a variety of different toxic agents. The major function of the GI tract is to process and absorb water and nutrients, while food is physically moved from the mouth to the colon, where nonabsorbable wastes are stored for periodic elimination. Studies involving the assessment of gastric diurnal toxicology using gastric mucosal integrity have revealed that there is indeed a time-related damage component caused by the well-characterized aspirin and other nonsteroidal anti-inflammatory agents. Nutrients that are absorbed fall into general classes, proteins, fats, and carbohydrates, the same general classes as for digestion. Differences of size, anatomy, histology, and histophysiology between the gastrointestinal tracts may also contribute in a profound fashion to differences in the absorption of xenobiotics across species. The canine liver is host to a number of different types of lesions and quite commonly both gross and microscopic findings are noted.