Treatment of Helicobacter pylori (H. pylori) infection is crucial for the management of prevalent digestive and more recently also extra-digestive disorders. Rising prevalence of clarithromycin resistance worldwide has accounted for a dramatic decline in the efficacy of standard triple therapies, which should not be prescribed, unless local clarithromycin-resistance is low (<20%) or culture confirms susceptibility to this antibiotic (i,e,; as tailored treatments). Bismuth-quadruple, sequential, non-bismuth quadruple (concomitant), dual-concomitant (hybrid), and levofloxacin-based regimens have been shown to overcome clarithromycin resistance and are now preferred empirical treatments achieving improved eradication rates (>90% in per protocol analysis). In the future, empiric use of both clarithromycin and levofloxacin is likely to become steadily more challenging as even these novel eradication therapies may be prone to the effect of increasing antibiotic resistance. Tailored treatment based on the individual characterization of H. pylori therapeutic susceptibility appears to be a reasonable future alternative, currently limited by the shortcomings of systematically performing H. pylori culture (invasive, expensive, time-consuming). However, recent advances in the genotypic detection of H. pylori susceptibility to antibiotics, and in pharmacogenomics, may represent a breakthrough in our future approach to tailored therapy. Until then, efforts to optimize empirical treatments should continue.