An effective Helicobacter pylori therapy reliably provides high cure rates in infections with susceptible strains. It is possible to predict the efficacy of any regimen if one knows the prevalence of antibiotic resistance for a regimen or for a specific patient. We show how to predict the outcome for current regimens and discuss the factors that undermine different regimens (i.e., their Achilles heel). In general, in Western countries, clarithromycin-containing triple and sequential therapy should be considered obsolete as empiric therapies. Preferred regimens are 14-day concomitant or bismuth-containing quadruple therapy. We provide details of how to identify a regimen for a patient or region that will reliably cure 90% or more as well as those that will reliably fail.