Infection with Helicobacter pylori remains a major healthcare burden, with persistently high prevalence rates, especially in less-developed countries. H. pylori infection is causally related to non-malignant and malignant gastroduodenal diseases, such as peptic ulcer diseases, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. Current international guidelines recommend a standard triple therapy as first-line therapy, including a proton pump inhibitor and a combination of amoxicillin and clarithromycin. Standard triple therapy has shown a decreasing efficacy over the years. The main reason is the increasing antibiotic resistance, particular to clarithromycin of H. pylori strains. Several new treatment options or modifications of already established regimens have been introduced to overcome treatment failure. In this article, we intend to report the reasons for treatment failure, and furthermore we give an overview of new treatment options as alternatives to the current treatment regimens. Finally, the strategy for the future is considered.