Helicobacter pylori is a Gram-negative bacterium that persistently colonizes the human stomach. Most H. pylori strains secrete a pore-forming toxin (VacA), which is unrelated to any other known bacterial toxins. The most extensively studied VacA activity is its capacity to stimulate vacuole formation in gastric epithelial cells, but the protein also causes many other cellular alterations. For example, the protein’s immunomodulatory activities enhance the capacity of H. pylori to persistently colonize the stomach. All H. pylori strains contain a vacA gene, but there is marked variation among strains in VacA toxin activity. This variation is attributable to strain-specific variations in VacA amino acid sequences, as well as variations in the levels of VacA transcription and secretion. H. pylori strains producing certain forms of the toxin are associated with an increased risk of gastric adenocarcinoma and peptic ulcer disease, compared to strains producing less active forms of the toxin. New insights into VacA structure, oligomerization, interaction with membranes, and activities will be discussed.