The increasing prevalence of antimicrobial resistance has warned clinicians to adopt new strategies for dealing with the H. pylori infection. The success of various therapeutic regimens has recently declined to unacceptable levels. To date, first line therapies (including concomitant therapy and hybrid therapy), second line therapies (including bismuth-containing quadruple therapy and levofloxacin-containing therapy), and third line therapy (culture-guided therapy) had been introduced. In the near future, treatment of H. pylori is entering into a completely new resistance era. In this setting, despite the recent progress, we may only be targeting the patients with problematic H. pylori. Local preference for antibiotic selection should be an inevitable article in each therapeutic regimen worldwide. Meanwhile, improving the patients' compliance protocols and observed side effects in suggested therapeutic regimens should be considered cautiously. The new strategies in treatment should be adopted based upon local resistance patterns, which requires physician's resistance about the recommended guidelines. Designing new therapeutic regimen, which contains most effective available antibiotics with less possible side effects and high patient compliance, represents a challenging task in treatment of H. pylori infections.