The use of animal models in the nonclinical assessment of safety of agents potentially affecting the gastrointestinal (GI) tract can be classified as being for one of two objectives. The inflammatory response is primarily an expression of the innate immune system, but this response also is an expression of the coordination between the complex innate and adaptive immune systems associated with the GI tract. New consideration is the difference in GI microbiomes of the potential model species, and how the relevance of these applies to the human species. Some studies are almost always not focused specifically on detecting adverse effects on the GI tract—rather, they are effectively broad screens for potential toxicity. Concern is that one needs to understand how effects seen in the GI tract of a model species are relevant (or not) to expectations of what should be expected in humans.