Eradication therapies for Helicobacter pylori evolved from monotherapy, through dual therapies and finally to bismuth-based triple therapies by the mid-1980s. The advent of proton pump inhibitors (PPI) and clarithromycin added a new impetus in the development of newer and often more effective regimens. Following large numbers of therapeutic trials, two broad groups of therapies stand out which consistently achieve over 90% eradication. Both are PPI-based. PPI/amoxycillin/clarithromycin twice daily therapy is the simplest but perhaps the most expensive. The 7-day quadruple (quad) therapy, consisting of a PPI and bismuth/tetracycline/metronidazole, is rapidly emerging as the "all rounder" therapy able not only to overcome metronidazole and clarithromycin resistance but to also have a consistently high eradication rate of well over 90%. Extensive clinical use of older and cut-down versions of combination therapies is resulting in a rising population of treated patients who continue to be infected with H. pylori, often resistant to further eradication attempts. Failure to recognise the need to use regimens which achieve high first-time eradication success will lead inexorably to an enlarging pool of patients with resistant strains and "difficult-to-eradicate" H. pylori.