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Quadruple therapy (with a proton pump inhibitor (PPI), metronidazole, tetracycline and bismuth) is generally reserved for second-line treatment; however, studies using this regimen for 7 days have found it to be effective even in metronidazole-resistant strains. Resistance is an ongoing problem with antimicrobial therapy but considerable progress has now been made into understanding the underlying genetic mechanisms of this process. Metronidazole resistance in Europe is usually in the range of 20–30% of strains but may be as high as 70% in some countries. One genetic mechanism involved is thought to be a mutation of the rdxA gene. Macrolide resistance appears to be on the increase in Europe, varying from 1% in some countries to 13% in others. The genetic mechanism involved has been shown to be a point mutation of a ribosomal RNA. Amoxicillin resistance is an emerging problem that has an adverse effect on eradication rates in clinical practice. Resistance has been shown to be caused by the absence of one of the four binding proteins in the cell wall. Few novel antibiotics have been developed for use in eradication therapy, although rifabutin, secnidazole and furazolidone have shown some success as part of combination therapy. Alternative therapies that have been tested include mucosal protective agents which have been used in place of a PPI in some eradication regimens with some success, and the somatostatin analog, octreotide, that has been used as part of quadruple therapy in place of a PPI and produced eradication rates of approximately 88%. The ultimate challenge is still to develop a safe and effective vaccine against Helicobacter pylori. Current and future research will also focus on identifying genetic targets for therapy, adhesion molecule analogs to prevent binding of the bacterium, and urease inhibitors. The current triple therapy treatment options available for the eradication of Helicobacter pylori infection are over 90% effective in susceptible organisms and there are very few medical conditions to which we can offer such efficacious treatment. Unfortunately, the recommendations made at consensus conferences are not always put into practice and physicians in primary care may be unaware of the true efficacy of eradication therapy. Treatment is very simple: three drugs, twice a day for 1 week. The main focus for both primary care physicians and gastroenterologists should be to reinforce the need for patient compliance, otherwise we will see an increase in antibiotic resistance. Patients should be prewarned that they may experience some mild side effects and should be encouraged to complete the course of treatment. The real challenge for the future will be the management of patients who do not respond to first-line treatment. This paper will focus on potential problems with therapy, such as antibiotic resistance, and possible future solutions, such as novel antibiotics and vaccines.