Over the past 30 years, multidrug regimens consisting of a proton pump inhibitor (PPI) and two or three antibiotics have been used in treating Helicobacter pylori (H. pylori) infection. In clinical practice, the optimal regimen to cure H. pylori infection should be decided regionally. Considering the first treatment, the Maastricht V/Florence Consensus Report and the American College of Gastroenterology Clinical Management Guideline highlight that in countries with low clarithromycin resistance rates (<15%), an empiric clarithromycin-based regimen can be used. In countries with high clarithromycin resistance rates or, in the American Guideline, with a previous exposure to clarithromycin, a bismuth-containing quadruple therapy (with metronidazole and tetracycline) is the first choice. In case of persistent infection, after a previous clarithromycin-containing regimen, this drug should be avoided in second line therapy. Options after initial eradication failure include tailored therapy (choosing antibiotic combinations based on antibiotic susceptibility testing), empiric bismuth-containing quadruple therapy or triple levofloxacin-based therapy. Encouraging data are reported, both for the first-line and for rescue treatments, with the use of a formulation of bismuth subcitrate potassium, metronidazole, and tetracycline contained in a single capsule, together with a PPI. Rifabutin- and furazolidone-based regimens should also be considered in rescue regimens. Vonoprazan, a new type of potassium-competitive acid blocker that produces more potent acid inhibition than PPIs, provides improved H. pylori eradication rates in combination with antibiotics. In this review, the authors provide an overview on the current knowledge on the treatment of H. pylori infection, with focus on therapeutic challenges in this field.