Helicobacter pylori infects one-half or more of the world population and causes chronic gastritis, peptic ulcer, and probably gastric cancer as well. The public-health impact of this infection is far from trivial. Chronic gastritis and peptic ulcer disease are common across populations. Gastric cancer rates have declined during this century, but this cancer remains second among causes of cancer deaths worldwide. Much has been learned about biological and clinical aspects of H. pylori, but key epidemiologic questions have not been answered. How infection results in diverse diseases, the precise modes of transmission, and a comprehensive solution to H. pylori as a public-health problem remain elusive. In this paper, we highlight methodologic challenges and outline an agenda for future research. Challenges include improving validation of detection methods and considering the limitations of these methods when interpreting epidemiologic data. The role of cofactors in H. pylori-induced diseases requires extensive exploration. Many intriguing areas of H. pylori research require the skills of epidemiologists. The discovery of an infectious etiology of common chronic diseases presents a promising opportunity for improving public health.