Gastric hyperacidity and ulceration of the stomach mucosa due to various factors are serious health problems of global concern. Although the mechanism of acid secretion from the parietal cells is now well understood, the processes involved in gastric ulceration are still not clear. Among the various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori and due to use of non-steroidal anti-inflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species, especially the hydroxyl radical. A number of excellent drugs, developed over the decades, have proven useful in controlling hyperacidity and ulceration although their long-term use is reported to be associated with various side effects. Hence the investigations continue with an objective to find a compound possessing anti-secretory, anti-ulcer and antioxidant properties which will serve as a therapeutic agent to reduce gastric hyperacidity and ulcers. This article describes the role of reactive oxygen species in gastric ulceration, briefly presents a note on the currently available drugs controlling them, and focuses on the role of melatonin, a pineal secretory product, in protecting against gastric lesions. In experimental studies, melatonin has been shown to be effective in reducing mucosal breakdown and ulcer formation in a wide variety of situations. Additionally, the low toxicity of melatonin supports further investigation of this molecule as a promising gastro-protective agent. Finally, we include a commentary on how melatonin research with respect to gastric pathophysiology can move forward with a view to eventually using this indole as a therapeutic agent alone or in combination with the existing drugs to control gastric ulceration in humans in order to increase their efficacy and / or to reduce their side effects.