Helicobacter pylori, a Gram-negative organism that survives in the deep mucus layer and attaches to the gastric surface cells, is estimated to be present in up to one-half of the US population. Chronic H. pylori infection causes chronic gastritis, peptic ulcer diseases and even gastric cancer. Cure of the infection leads to healing of gastric inflammation, prevention of development of peptic ulcer, as well as accelerated healing of peptic ulcers, and prevention of ulcer recurrence. Treatment of H. pylori has undergone substantial evolution over the past decade. Despite the in vitro susceptibility, results from single or even dual drug therapy is typically unsatisfactory and the best therapy is yet to be defined. The best current therapies for H. pylori infection consist of a proton pump inhibitor (PPI) or ranitidine bismuth citrate and two antibiotics (triple therapies), or bismuth, tetracycline, metronidazole and a PPI (quadruple therapy). Clarithromycin is one of the most useful antimicrobials against H. pylori. It is an acid-stable macrolide with a broad spectrum of antibacterial activity, well absorbed with a wide tissue distribution and with mild side effects. Clarithromycin has a low minimum inhibitory concentration (MIC50) for H. pylori and its effect is potentiated by acid inhibition. When combined with a PPI or ranitidine bismuth citrate and amoxicillin or metronidazole, eradication rates of more than 95% can be achieved with susceptible organisms. However, the prevalence of primary and acquired clarithromycin resistance, which is due to mutations within a conserved loop of 23S rRNA of H. pylori, is increasing. In practice, the presence of clarithromycin resistance usually implies reduced success when clarithromycin-containing regimes are used. There is a need for improved therapies for H. pylori where antibiotic resistance is less of a problem.