Treatment of Helicobacter pylori infection has become a problem in many clinical settings. Eradication rates are at the lowest levels seen in the past decade and are likely to fall further as antimicrobial resistance becomes more prevalent worldwide. Culture of H. pylori and antimicrobial sensitivity testing is still not generally available; therefore treatment strategies that are selected based on information that is specific to the individual patient are often not possible. Current strategies for treatment in most Western countries consist of initial therapy with a combination of a proton pump inhibitor therapy with amoxicillin and clarithromycin, with quadruple therapy reserved for failures. Sequential therapy is an attractive new alternative for initial treatment and may offer an alternative to conventional therapies. The choice of initial therapy is in a state of flux and this article will discuss alternative treatment strategies that clinicians may use in this difficult environment.