Successful Helicobacter pylori eradication therapy remains a challenge in medical practice. Currently, a proton pump inhibitor-based triple therapy containing clarithromycin, amoxicillin or nitroimidazole for 7 days is the recommended first-line treatment approach with an expected eradication success rate of approximately 80%. As a second-line treatment option in the case of failure, a ranitidine bismuth citrate-based quadruple therapy is currently recommended curing another 80% of patients, leaving a subset of patients with persistent H. pylori infection. For these patients, promising rescue options have been evaluated including regimens that contain rifabutin, quinolones, furazolidone or high-dose amoxicillin. The role of susceptibility testing is still under discussion. It is not generally recommended prior to first-line treatment but guidelines propose a role for culture and antibiotic sensitivity testing after failure of the second attempt. Meanwhile, data on the geographic distribution of resistance pattern are available and may guide therapeutic decisions with regard to the combination of antibiotics chosen for the individual patients aiming at 100% cure rate in each individual patient.