Helicobacter pylori is a common gastric pathogen associated with multiple clinical syndromes, including cancer. Eradication rates of H. pylori remain suboptimal despite the progress made in the past few decades in improving treatment strategies. The low eradication rates are mainly driven by antibiotic resistance of H. pylori. Non-invasive molecular testing to identify patients with antibiotic-resistant H. py-lori represents a promising therapeutic avenue, however this technology currently remains limited by availability, costs, and lack of robust validation. Moreover, there is insufficient evidence to demonstrate that resistance-testing-based treatment approaches are superior to appropriately designed empiric strat-egies. Consensus guidelines recommend use of proven locally effective regimens; however, eradication data are inconsistently generated in several regions of the world. In this review, we describe several clinical factors associated with increased rates of antibiotic resistant H. pylori, including history of previous antibiotic exposure, increasing age, female gender, ethnicity/race, extent of alcohol use, and non-ulcer dyspepsia. Assessment of these factors may aid the clinician in choosing the most appropriate empiric treatment strategy for each patient. Future study should aim to identify locally effective therapies and further explore the clinical factors associated with antibiotic resistance.