The essential nature of many metals is counterbalanced by the toxic effect that they can exert on both the eukaryotic and prokaryotic cell when not properly controlled. As such, virtually all organisms have developed regulatory systems that are required to maintain metal ion homeostasis. Helicobacter pylori is arguably the most successful bacterial pathogen in the world; the bacterium colonizes more than 50% of the worlds population. H. pylori lives in the acidic environment of the stomach and causes a persistent infection that results in disease sequelae such as gastritis, iron-deficiency anemia, ulcer disease and gastric cancer. A requirement of colonization is that the bacterium successfully competes with host cells for available metal ions. As such, it is perhaps no surprise that several crucial colonization factors utilize metal as an essential cofactor. Recent investigations into the absolute requirement for different metal ions and the need to manage their use have shown that metal ion homeostasis is achieved by H. pylori through the utilization of an intricate regulatory cascade that ensures metal uptake without toxic side effects. Herein we discuss this cascade, the role that individual metal ions play in H. pylori colonization and disease and the possibility that these metal homeostasis cascade components may serve as good targets for rational drug design to eradicate H. pylori infection.