There are a number of major changes that are ongoing in terms of H. pylori therapy in the US. The indications for diagnosis have expanded. We have new methods for rapid diagnostic testing. Some of our prior diagnostic methods are now obsolete (e.g., RUT). Susceptibility testing is now available in the US the major commercial laboratories USCH, Mayo Clinic Laboratory, Quest, and Labcorp provide culture of gastric biopsies. American Molecular Laboratory does Next Generation Sequencing for resistance to 6 antibiotics for fresh and formalin fixed gastric biopsies and stools. Many of our previously favorite antibiotic regimens are no longer effective because of increasing resistance. We need to reconsider our approach and treatment. Now it is recognized that choice of an empiric therapy must be based on what works best locally. In most regions: clarithromycin and levofloxacin resistance preclude their use as empiric therapy. The three basic rules of effective therapy are to utilize only therapies that are highly successful locally (preferably cure rates of >95% or at least >90%, utilize only regimens optimized to maximize efficacy (i.e., optimized for acid suppression, antibiotic doses and dosing intervals, duration of therapy etc) and closely monitor treatment effectiveness over time by always obtaining tests-of-cure and using that data to remain current regarding which therapies are locally effective. The keys to curing the infection are to treat it as an infectious disease and rely on what works locally instead of guideline that have no relevance to local conditions. All guidelines must be developed locally.