Seven years after the defeat of Handsome Jack, twin siblings Troy and Tyreen Calypso have formed the Children of the Vault, a violent cult built from Pandora's bandit factions. The twins, both Sirens born conjoined, seek to absorb the power of alien Vault monsters across the galaxy and open the Great Vault, a prison containing an interdimensional creature called the Destroyer. A team of new Vault Hunters, recruited by the Crimson Raiders and their leader Lilith, must pursue the Calypsos across multiple planets, forging alliances with old friends and new while racing to prevent the twins from unleashing a force capable of consuming the universe.