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The Helicobacter pylori vacuolating cytotoxin (VacA) is a secreted pore-forming toxin and a major virulence factor in the pathogenesis of H. pylori infection. While VacA is present in almost all strains, only some forms are toxigenic and pathogenic. While vacA and its genotypes are considered as markers of H. pylori-related diseases or disorders, the pathophysiological mechanisms of VacA and its genotypes remain controversial. This review outlines key findings of publications regarding vacA with emphasis on the relationship between vacA genotypes and the development of human disease.