Vibrio cholerae, the causative agent of cholera, has triggered seven pandemics, with the seventh pandemic emerging in 1961. The success of seventh pandemic El Tor (7PET) V. cholerae as a human pathogen is linked to its acquisition of mobile genetic elements (MGEs) like the CTXΦ prophage and Vibrio pathogenicity island 1 (VPI-1). Additional MGEs, including VPI-2 and the Vibrio seventh pandemic islands (VSP-I and VSP-II), are thought to have further enhanced the pathogen’s virulence potential. However, recent research suggests that these MGEs serve as reservoirs for defence systems, which may represent their main role. In this review, I highlight conserved defence systems in the 7PET lineage, including a cyclic-oligonucleotide-based antiphage signalling system, DNA defence modules (DdmABC and DdmDE), an anti-viral cytidine deaminase, and diverse restriction systems (T1RM and TgvAB). I also discuss two defence systems encoded on a VSP-II variant unique to West Africa–South America lineage strains and the chromosomal integron, recently recognized as a biobank for defence systems. Lastly, I address the challenges posed by the scarcity of V. cholerae phages, which often require studying these systems in heterologous hosts like Escherichia coli , leaving their natural triggers and defence roles against predatory phages of 7PET V. cholerae largely unexplored. This article is part of the discussion meeting issue ‘The ecology and evolution of bacterial immune systems’.