It is now accepted that peptic ulcer disease, whether duodenal or gastric, is one manifestation of infection with the bacterium Helicobacter pylori. This realization has revolutionized the management of peptic ulcer disease and changed the dictum from no acid no ulcer, to no H. pylori, no ulcer. When confronted with a patient with peptic ulcer disease, the physician must now ask whether H. pylori infection is present and if so, attempt to cure it. The gastric milieu is a very difficult environment for effective antimicrobial therapy. Nevertheless, current multi-drug antimicrobial therapy can be expected to cure the infection in more than 80% of patients. Cure of the infection is associated with a very low rate of recurrence. The continued risk of serious disease or disease complications associated with treatment failure and the availability of the urea breath test to non-invasively assess the results of therapy suggest that post therapy assessment should be routine. Because H. pylori infection causes structural and functional damage to the stomach and is associated with a lifetime risk of peptic or gastric cancer of approximately 16 and 1%, respectively, the infection should be treated whenever it is diagnosed. This paper reviews the current approach to therapy of patients with H. pylori infection, the effective antimicrobial drug combinations end the factors that predict treatment failure. Emergence of antimicrobial resistance may soon undermine the effectiveness of current drug regimens and require pretreatment culture and sensitivity testing as well as development of new drugs and drug regimens.