Helicobacter plays a central role in the pathogenesis of several gastric diseases and its eradication has a therapeutic or prophylactic effect in many clinical situations. However, treatment of Helicobacter infection can be challenging and the frequently recommended clarithromycin based triple therapy fails in more than 20% of patients. Reasons for treatment failure include antibiotic resistances and bacterial persistence in an acidic stomach, for instance due to rapid metabolization of the proton pump inhibitor by the host. Therapeutic efficiency can be improved by a therapy tailored for an individual patient and the respective pathogen. In an alternative approach the antibiotic therapy can be intensified leading to a sequential or concomitant therapy. These and other strategies tested only in single studies can achieve eradication in 90 % and up to over 95 % of patients, respectively, and should be used more often in clinical practice.