The stomach, intestines, and digestive glands produce acid and various enzymes, including pepsin, that break down and digest the starch, fat, and protein in food. The stomach itself is composed mostly of protein and must be protected from the same acid and enzymes, or it too can be attacked and broken down. Ulcers develop when an imbalance occurs between the digestive juices used by the stomach to break down food and the various factors that protect the lining of the stomach and duodenum (the part of the small intestine that adjoins the stomach). A peptic ulcer is an open sore or raw area in the lining of the upper part of the small intestine (duodenal ulcer) or the stomach (gastric ulcer). They average between one-quarter to one-half inch in diameter. In the US, duodenal ulcers are three times more common than gastric ulcers.

The primary digestive juices, hydrochloric acid and pepsin, are powerful substances necessary for breaking food down for use by the body. Acid is always present in the stomach, but, except at meal times, in relatively small amounts. A common misbelief is that excess acid is solely responsible for producing ulcers. Hydrochloric acid, secreted in the stomach, does indeed play a part in the development of ulcers, but it is not the only culprit. Pepsin, the other major digestive fluid, is an enzyme that breaks down whatever proteins are presented to it, including, if exposed, the stomach's own tissues.

Acid output in patients with duodenal ulcers does tend to be higher than normal, but in those with gastric ulcers, acid production is usually normal or lower. Abnormally large amounts of acid secretion occur in rare situations, such as in the genetic condition known as Zollinger-Ellison syndrome, in which acid is stimulated by tumors located in the pancreas or duodenum.

In order for pepsin and hydrochloric acid to cause damage to the stomach or duodenum, however, the stomach's defense system must be altered or damaged. The mucous layer, which coats the stomach and duodenum, forms the first line of defense against acid and pepsin. In addition, the body secretes bicarbonate into the mucous layer, which neutralizes the acid. So while the contents of the stomach may be highly acidic, the stomach's own tissues are normally only slightly acidic. Other factors in the defense system of the intestinal tract are hormone-like substances known as prostaglandins, which help keep the blood vessels in the stomach dilated, ensuring good blood flow and protecting against injury. Prostaglandins are also believed to stimulate bicarbonate and mucus production. If any of these defense mechanisms are disturbed, and acid and pepsin are allowed to attack the stomach lining, an ulcer can result.