Resistance development is a significant clinical problem in Helicobacter pylori and represents the major cause of treatment failure. Today the problem is most focused on the macrolide clarithromycin that is an essential component of the H. pylori treatment. Traditional methods for resistance determination, e.g., disc diffusion tests or E-tests, could in the next 5 years be replaced by DNA-based methods. The most commonly used molecular methods available today are not used in the daily routine work. Rapid and reliable DNA-based methods for prediction of antimicrobial resistance phenotype are currently available within research. As fabrication costs reduce and validated targeted assays are developed with easy hands-on procedures, it is most likely that such assays will become important tools for clinical diagnosis of resistant H. pylori strains.