Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face Helicobacter pylori treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final – overall – eradication rate. After failure of a combination of proton pump inhibitor (PPI), amoxicillin, and clarithromycin, the use of empirical quadruple therapy (PPI–bismuth–tetracycline–metronidazole), has been generally used as the optimal second-line therapy. Even after two consecutive failures, several studies have demonstrated that H. pylori eradication can finally be achieved in almost all patients if several “rescue” therapies are consecutively given. It seems that performing culture even after a second eradication failure may not be necessary, as it is possible to construct an overall strategy to maximize H. pylori eradication, based on the different possibilities of empirical treatment (when antibiotic susceptibilities are unknown). Thus, if one does not want to perform culture before the administration of the third treatment after failure of the first two, different empirical treatments exist, including regimens based on: 1, amoxicillin (amoxicillin–PPI at high doses); 2, amoxicillin plus tetracycline (PPI–bismuth–tetracycline–amoxicillin, or ranitidine–bismuth–citrate–tetracyline–amoxicillin); 3, rifabutin (rifabutin–amoxicillin–PPI); 4, levofloxacin (levofloxacin–amoxicillin–PPI); and 5, furazolidone (furazolidone–bismuth–tetracycline–PPI).