In this Star Trek: Voyager trilogy, the crew of Voyager discovers a region of space that has been used for experiments by the Nacene, the race responsible for their presence in the Delta Quadrant in the first place. Having discovered a space station containing various information about the Nacene, the crew learns that the Caretaker, Suspiria, and numerous other Nacene are exiles, living away from their people as a punishment for tampering with the cosmic strings that the universe consists of; the other Nacene believe it is a sacred duty to care for the strings (although Q told the crew that the Nacene were exaggerating and the strings would be fine on their own).

When Voyager came into possession of the Key that would allow the Nacene to return to Exosia, their home dimension from which they were exiled, a Nacene attempted to infiltrate Voyager by altering the crew's memories to make them believe that the Nacene was CaptainJaneway's sister, who had been with them on the mission from the beginning. However, despite her attempts to escape attention, she was quickly discovered thanks to Naomi Wildman and Harry Kim, whose molecular structures were slightly out of sync with the rest of the crew due to them both coming from the duplicate ship created in "Deadlock", and were thus immune to her tampering (she even activated a backup version of The Doctor to try and escape attention, but the two programs were so different that the crew soon realized that something was wrong).

During their research into the space station, Q rescues Tom Paris and Harry Kim from an accident and subsequently recruits them to help him track down an Ocampa/Nacene hybrid who holds the key to repairing damage that has recently been caused to the space/time continuum. During this appearance, Q reveals that omnipotent beings are actually rather fond of games of choice and chance, as it is only under these conditions that beings such as Q can feel the thrill of not being in total control.

The Nacene launched an assault on Voyager to regain the Key, but Voyager was able to hold them off, using the neurotoxin that Tuvok had developed in their encounter with Suspiria. The Doctor becomes trapped in Exosia when the rift is briefly opened, causing photonic energy to be drawn in, and then gets sent into Ocampa's distant past by a Nacene who wanted the Doctor to prevent the birth of a Nacene-Ocampa hybrid that it perceived as a threat. Developing a fondness for the hybrid's mother, an Ocampan general who reminds him of Kes, the Doctor chooses not to prevent the birth, and the Nacene-Ocampa hybrid was able to stabilize reality and negotiate peace between the two Nacene factions (after the hybrid's future self was tracked down by Tom Paris and Harry Kim, aided by a young Q). Aided by Kes, the Nacene evolved to a higher stage of being, as Kes and her "son" – only Kes' body could cope with the strain of giving birth to the hybrid, although another Ocampan contributed the genetic information – returned to Ocampa to repair the ecological damage that the Nacene caused long ago, and, three years later, rain finally fell on Ocampa once more. However, as a result of the rift being opened, all photonic energy in this region of space has been drained away, with a new history being created to 'explain' the change, as well as Janeway's exposure to the Key leaving her vulnerable to certain 'mood swings' in the future, with her only chance at recovery being a continued ignorance of the events that have taken place.