Eradication rates of first-line triple therapy for Helicobacter pylori infection have fallen in the recent years. The main reasons for treatment failure are poor compliance due to complicated treatment regimens and the emergence of antibiotic-resistant strains of H. pylori. Treatment failure is a cause for concern with regard to the complications of H. pylori infection, which include gastric and peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma. This review describes considerations for optimizing standard first-line triple therapy, as well as alternatives to the standard first-line treatment, such as bismuth quadruple therapy, sequential therapy, concomitant therapy and hybrid therapy. Studies using levofloxacin-based and rifabutin-based regimens for the treatment of multiresistant infections have also been reviewed. The current most up-to-date systematic reviews and meta-analyses comparing the efficacy of these treatments have been discussed, in light of the recent antimicrobial susceptibility testing data, regional antibiotic resistance rates and the Maastricht IV guidelines on the management of H. pylori infection.