The discovery that the bacterium Helicobacter pylori (H. pylori) lives in the stomach has rendered out-of-date the concept of inhospitality of the gastric environment. H. pylori is able to survive in this organ through mechanisms of acid resistance and colonization factors. The prevalence of H. pylori infection varies depending on age, socioeconomic class, and country. Currently, in the context of a decreased trend in H. pylori prevalence, it is estimated that about 50% of the world's human population are carriers of the microorganism, with a higher rate in developing countries than in developed countries. In this review, the authors provide an overview on the current status of knowledge on the clinical aspects of H. pylori infection, with a focus on diagnostic and therapeutic challenges. In particular, the choice of the test to diagnose H. pylori infection, defined as invasive or non-invasive based on the need or not of biopsy specimens obtained during an endoscopy, depends on the clinical context. Regarding bacterial eradication, it is important that treatment should be decided locally on the basis of local antibiotic usage, documented antibiotic resistance and outcome data. For patients having previously received a clarithromycin-containing regimen, this drug should be avoided as a second-line therapy. In this case, the tailored therapy (to test clarithromycin susceptibility before prescribing drugs) or the so-called quadruple therapy, and triple levofloxacin-based therapy should be proposed. Rifabutin- and furazolidone-based treatments should be reserved for further treatment.