Helicobacter pylori continues to present therapeutic challenges for clinicians across the world. This review article aims to consolidate current knowledge of H. pylori infection with a particular emphasis on treatment strategy and summarizes important studies regarding H. pylori therapy published from April 2020 to March 2021. Proton pump inhibitor (PPI)-amoxicillin dual therapy can be considered when antimicrobial susceptibility testing cannot be performed. Triple therapy for 14 days may be sufficient in some regions with low clarithromycin resistance. Less expensive sequential and hybrid therapy were more successful and as well tolerated as the currently recommended concomitant therapy and should be favored as non-bismuth quadruple regimens. Bismuth quadruple therapy with tetracycline and modified bismuth quadruple therapy with amoxicillin were highly effective and safe in H. pylori eradication and should be kept in mind as H. pylori first-line therapy in regions with high resistance to clarithromycin. These therapies also have a good performance as second-line and third-line regimens and revealed a satisfactory eradication rate as rescue therapy. In patients allergic to penicillin, quadruple regimen with PPI + bismuth + tetracycline and metronidazole seems to be a good option. Rifabutin and nitazoxanide-based regimens are safe and effective as a salvage therapy in patients who have failed prior treatments. Superiority of vonoprazan in eradicating H. pylori was observed, notably on the resistant strains. The drug-resistance phenomenon in H. pylori underlines the need for novel strategies to improve the eradication rate, especially susceptibility-guided therapy.