The gastrointestinal tract (GI), which accounts for one of the largest organ systems in the body, is typically associated with absorption of nutrients and excretion of excess waste derived from food consumption. The GI tract has defense mechanisms to protect the body from toxicants, but these are occasionally breached, resulting in compound-induced toxicity. This chapter provides background information on specific drugs and drug classes which are known to be toxic to the GI tract. The drugs include Rotashield, Lotronex, and Slow-K potassium chloride tablets, ethanol, bisphosphonates, opiates, and non-steroidal anti-inflammatory drugs. Ethanol may elicit a variety of stomach- and intestine-specific toxicities, including mucosal damage, altered gastric acid secretion, changes to the intestinal microbiome, altered motility and absorption of nutrients from food, and possible carcinogenesis. Upper GI toxicities include dyspepsia, damage to the protective gastric and duodenal mucosa, asymptomatic mucosal lesions, gastric and gastroduodenal ulcers, GI bleeding, and in some cases, death.