Helicobacter pylori infection still represents a major health issue, especially in developing countries, with an estimate of 4 billion of infected subjects in 2015. The increase of antibiotic resistance has undermined the efficacy of standard triple therapy leading to more complex regimens. This review summarizes recommendations of international guidelines and reports the most recent evidence from meta-analyses and clinical trials on the treatment of Helicobacter pylori infection. The choice of H. pylori eradication regimen should be based on the local prevalence of clarithromycin resistance and the previous use of macrolides. Quadruple therapies (bismuth quadruple and concomitant) are the recommended regimens for the first-line treatment; a 14-day clarithromycin-containing triple therapy is suggested in areas with low prevalence of clarithromycin resistance and in patients without previous use of macrolides. Data on the efficacy of sequential therapy against clarithromycin resistant H. pylori strains are contradictory, and its use in the treatment of H. pylori infection is generally discouraged. Second-line treatments include levofloxacin-containing triple therapy and bismuth quadruple therapy. Probiotic supplementation should be used with the aim to reduce antibiotic-related adverse events. Recent evidence would support current guideline recommendations for the treatment of Helicobacter pylori infection.