During the last decade, short-term therapeutic regimens were developed for H. pylori infection treatment. Although these regimens achieve high efficacy, therapeutic failure is a growing problem in the daily clinical practice. Factors leading to therapeutic failure include compliance and bacterial resistance, especially to clarithromycin and imidazoles, among others. When there is a therapeutic failure, post therapy based on clarithromycin, quadruple therapy (bismuth salt, tetracycline, furazolidone and proton pump inhibitor) or triple therapy, with association of levofloxacin, proton pump inhibitor and furazolidone or amoxicillin, are recommended, with eradication rates around 80%. This review present the main factors involved in H. pylori infection treatment failure and some new therapeutic approaches.