Large cell size is not restricted to a particular bacterial lifestyle, dispersal method, or cell envelope type. What is conserved among the very large bacteria are the quantity and arrangement of their genomic resources. All large bacteria described to date appear to be highly polyploid. This review focuses on Epulopiscium sp. type B, which maintains tens of thousands of genome copies throughout its life cycle. Only a tiny proportion of mother cell DNA is inherited by intracellular offspring, but surprisingly DNA replication takes place in the terminally differentiated mother cell as offspring grow. Massive polyploidy supports the acquisition of unstable genetic elements normally not seen in essential genes. Further studies of how large bacteria manage their genomic resources will provide insight into how simple cellular modifications can support unusual lifestyles and exceptional cell forms.