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Archer awakes from destroying the Xindi superweapon in the U.S. circa 1944 as a prisoner of Nazis controlling New York City. But he escapes with the help of American insurgents. The crew aboard Enterprise seeks answers for their journey back in time and the changes to Earth's history. They find a dying Daniels on board who tells T'Pol about an alien faction of the Temporal Cold War led by Vosk, now allied with the Nazis altering the events of World War II. Archer, T'Pol, and the Enterprise must defeat the aliens and restore the timeline to return to their time.

Vosk and his people altered Earth's past, threatening to destroy many futures. Frustrated by limited Nazi technology, Vosk offers to return Trip and Mayweather to the Enterprise if Archer assists Vosk in creating his time machine. Vosk releases the prisoners, with Suliban agent Silik taking Trip's form; Silik also needs to stop Vosk. Meanwhile, Alicia's comrades in Nazi-occupied New York learn of Archer's space vessel on the eve of an Allied counterattack. Archer, Silik, and Alicia's comrades attack Vosk's time machine facility to disable its protective shield. Their efforts allow Enterprise to destroy the facility. Daniels returns to tell Archer that the timelines are restored and sends Enterprise home.

The Enterprise finally returns to Earth with great fanfare, and the weary crew members face repercussions of their journeys, both positive and negative. But the novelty quickly disappears for Archer, forced to vacation after a heated exchange with a Vulcan official. Also, Trip accompanies T'Pol to Vulcan, where he meets her mother, T'Les, but when T'Pol reconsiders marriage to her former fiance, Koss, Trip questions their relationship. The Xindi scare causes increased violent incidents against alien species on Earth, and Reed worries about Phlox's safety.

When genetically engineered humans left over from the Eugenics Wars hijack a Klingon ship, the Klingons threaten war with Earth. Archer enlists the criminal Dr. Arik Soong, the Augments' creator and "father," to help hunt them down.

Cold Station 12 is a medical research facility where hundreds of genetically enhanced embryos left over from the Eugenics Wars are still stored. Arik Soong leads his band of Augments to the scientific outpost, intending to retrieve the embryos, bring them to life, and create a superhuman army of Augments. On the raid, Soong realizes just how ruthless his "children" have become and threatens to release the deadly pathogens stored on-site if anyone interferes.
 

The Enterprise crew cautiously pursues Dr. Arik Soong and his superhuman Augments across hostile Klingon space toward a hidden planet where he intends to raise his Augment army. But in defiance of their "father" Soong, Malik devises a heinous plot to use a bioweapon against a Klingon colony planet, undoubtedly leading to interstellar war, to safeguard the Augments from Enterprise and further Starfleet interference. Malik's rash proposal leads to a rift with Soong.

The crew joins forces with Vulcan authorities to investigate a deadly bombing of Earth's embassy, which may be the work of a sect devoted to the logical teachings of Surak, the father of Vulcan philosophy.

The Syrranites subject Archer to a potentially lethal mind-meld after learning that information about Surak was placed in his head. Meanwhile, Vulcan officials plot the dissidents' destruction.

As Vulcan prepares for war, V'Las sends a commando team to eliminate Archer, T'Pol and T'Pau, while Soval risks his sanity to warn the Andorians of the impending attack.

Emory Erickson, the inventor of the transporter, boards the Enterprise to test new transporter upgrades. He also enlists Archer's help with a risky experiment resulting in a crew member's death. This forces Emory to reveal the real purpose of his test, searching for and retrieving his lost son.

Two non-corporeal Organians possess the bodies of various crew members to observe humanity's reaction to tragedy. The curious beings study the response of the Enterprise crew to a fatal silicon-based viral infection contracted by Trip and Hoshi during an away mission. Phlox works feverishly for a cure. Will the "advanced" aliens learn anything about human empathy and compassion? 

While escorting a Tellarite ambassador to the neutral planet Babel for a peace conference with the Andorians, the Enterprise is attacked after answering a distress call from Shran. A secret Romulan vessel attacks ships on all sides, trying to halt any chance for peace. 

Archer tries to unify the Andorians, Tellarites, and Vulcans in a plan to capture a remote-controlled Romulan marauder ship threatening to destabilize the region. But, a desire for vengeance interferes with Archer's attempts to ally Shran and the Tellarites, where Archer and Shran fight to the death, almost. Trip and Reed probe the inner workings of the unmanned Romulan warship and must outwit their captors to escape.

Archer and the crew try to prevent the Romulans from starting an intergalactic war. He visits Shran's icy homeworld to find an Andorian subspecies called the Aenar to determine their connection to the marauder destroying ships in the region. The Aenar are telepaths who could gain control of the Romulan drone vessels.

Enterprise visits Earth for the launch of its sister vessel Columbia, where Trip prepares for her maiden voyage as her new chief engineer. Meanwhile, Klingons kidnap Phlox and force him to help them find a cure for a mutated virus that threatens their species.

With Columbia's help, the Enterprise crew grapples with the sabotage left by Klingon Augments as they pursue the truth behind Dr. Phlox's kidnapping. Trip rejoins Enterprise on a desperate mission to rejuvenate her warp drive. Then both ships head deep into Klingon space to find Dr. Phlox. Antaak convinces Phlox to cooperate with the Klingons and help find a cure for the mutated virus ravaging one of their outposts.

As a gift for negotiating a deal with the Orion Syndicate, an Orion pirate persuades Archer to accept three alluring Orion slave women. But the captain's good-faith gesture has terrible results when the trio wreaks havoc within the ship, seducing all the men on board.
 

An amoral, imperialistic version of the Enterprise crew exists in a dark alternate universe. Commander Archer of the Terran Empire Enterprise mutinies against Captain Forrest to investigate an anomaly in Tholian space and capture a future Earth ship. The Star Trek episodes "Mirror, Mirror" and "The Tholian Web" inspire this mirror-universe tale.

In the mirror universe, power-hungry Archer and the crew use the 23rd-century Defiant to thwart a Tholian attack and its advanced weaponry to put down a rebellion setting their sights on seizing control of all of Earth's Terran Empire. But first, he must rid the ship of a deadly Gorn stowaway.

Archer and the crew are on Earth for a historic conference at Starfleet Headquarters to establish an interplanetary coalition. But the plans are menaced by a fanatical xenophobe, John Frederick Paxton. He leads Terra Prime, an underground Human isolationist movement plotting against the government and threatening to undermine the talks. This radical faction opposes the increasing number and influence of aliens on Earth and advocates expelling all non-Humans from Earth and the rest of the Sol system.

Determined to scorch Starfleet Command in San Francisco if Earth refuses to abolish a proposed interplanetary alliance and make all aliens leave Earth immediately, Paxton blackmails Trip into modifying his doomsday weapon, the Verteron array on Mars. Archer and a handpicked team infiltrate Terra Prime's Mars headquarters to stop Paxton. Hoshi takes command of Enterprise as a traitor lurks within the crew. Elsewhere, the origin of Trip and T'Pol's child is revealed.

Commander Riker interacts with Archer's crew in a hologram of their final mission as he deals with a dark secret from his past. Six years after the Terra Prime incident, an emotional Captain Archer and the crew return to Earth to decommission Enterprise and sign the charter for the Federation, the new alliance of planets they helped forge. Enroute, Archer agrees to help his old ally Shran retrieve his daughter as the captain prepares a speech to celebrate the Federation's establishment.