Abstract: Background: Discoveries in the past two decades have continued to improve our understanding of the pathophysiology of peptic ulcer disease and animal models have played a significant role to define the basic mechanisms of gastric mucosal defense and repair. In the early 20th century, peptic ulcer disease was related to excessive acid secretion resulting from stressful lifestyle. The importance of the interaction of acid and pepsin in the formation of peptic ulcer disease remained unclear until the second half of the 20th century. With the introduction of histamine type 2 receptor antagonists (H2 receptor antagonists) in the 1970s, progress was made in reducing acid secretion and providing relief of symptoms. With further advancements in medical research, it is now well recognized that use of nonsteroidal anti-inflammatory drugs (NSAIDs) contribute to the development of peptic ulcer disease. Moreover, the identification of the role of a bacterium, Helicobacter pylori (H. pylori) in the pathogenesis of acid-peptic diseases, its elimination with antimicrobial drugs could effectively cure the disease stimulated new approaches to prevention and therapy. These advances in the discovery of novel and more effective anti-ulcer therapeutics is due to the introduction of a larger number of newer experimental methods to evaluate their anti-ulcer activity in different types of gastro-duodenal ulcers and simultaneously to study their mechanism of action. Several in vivo models of gastric damage have been well characterized and are the primary tools used by gastrointestinal physiologists, pharmacologists and pathologists to study new mechanisms of pathogenesis and new pharmacological targets for ulcer disease. Conclusion: This review aims to highlight some of the new and currently used experimental models that are used for the evaluation of gastric and duodenal anti-ulcer and gastric cytoprotective activity of novel anti-ulcer agents.