H. pylori eradication following standard triple therapies is decreasing worldwide, mainly due to an increased prevalence of bacterial resistance against antibiotics. Therefore, to cure such an infection remains a challenge for clinicians. This paper aimed to review the currently available therapeutic approaches, for which large and consistent data exist in literature, in order to update H. pylori management in the clinical practice. According to the updated European Guidelines, the first-line therapy should be chosen based on the prevalence of clarithromycin resistance. A 7-day triple therapy should be employed if clarithromycin resistance is lower than 15-20%, whilst this regimen should be prolonged to 14 days where resistance is higher. A 7-day quadruple therapy is suggested as second-line treatment. However, quadruple therapy is no more available in Italy. According to the forthcoming Italian Guidelines, a new "therapeutic package" could be used, including a 10-day sequential regimen as first-line therapy and a 10-day levofloxacin-based regimen as re-treatment. The sequential regimen (5-day dual plus 5-day triple therapy) achieved an eradication rate constantly >90% in several Italian studies, being more effective than standard triple therapy, even in patients with clarithromycin resistant strains.