Triple therapy including clarithromycin, amoxicillin, and a proton pump inhibitor (PPI) has been recommended as the treatment of choice for Helicobacter pylori eradication. This regimen is now challenged by an increasing level of clarithromycin resistance that jeopardizes the treatment success. When clarithromycin resistance has been detected, or when its rate is known to be high in the geographic area, this drug cannot be used. It can be replaced by metronidazole, the resistance of which has a limited clinical relevance. Another option is to prescribe tetracycline and metronidazole with a PPI or ranitidine bismuth citrate. New antibiotics such as levofloxacin or rifabutin can also be used in combination with amoxicillin and a PPI. Probiotics can be added to all of these regimens to improve compliance by decreasing adverse events. But some authors advocate a quadruple therapy as a first-line treatment. Solutions to improve the limitations of this last regimen are now being proposed. Clarification of the controversial treatment indications such as gastroesophageal reflux disease or prevention of nonsteroidal anti-inflammatory drug gastroduodenal symptoms has been made. The question of prevention of gastric carcinoma by H. pylori eradication remains unanswered.