Six weeks into the Delphic Expanse, Captain Archer and his crew learn of a Xindi working at a mining colony, and set out to track him down and gain information about the mysterious race. But when Trip and Archer get caught in a deadly trap, Enterprise's newest crew members, a squad of Military Assault Command Operation soldiers (MACOs), must rush to free them. Meanwhile, T'Pol suggests an intriguing Vulcan cure for Trip's vivid nightmares of his sister's death.
The mission to find the Xindi takes a grim turn when Enterprise is crippled by inexplicable, destructive spatial anomalies that distort the laws of physics. With systems down, Ventaxian pirates board and raid valuable supplies from the ship. The crew captures one of the alien marauders and a determined Archer interrogates the prisoner.
Their ongoing quest for the Xindi leads the Enterprise crew to a tropical alien world where Archer, Reed and Hoshi are exposed to a highly contagious virus that transforms their bodies and minds into those of the long extinct alien inhabitants of the planet.
Rescued by Archer from an alien bazaar, a captivating slave girl, Rajiin, uses her erotic, hypnotic mental powers on the crew to steal data on humans for her Xindi overlords. But when her deception is discovered, Archer throws her in the brig, forcing the Reptilian Xindi to storm the ship, weapons blazing, to spring her free.
Meanwhile, Trip and T'Pol initiate a dangerous experiment to insulate the ship from further destruction from strange physical phenomena in the Delphic Expanse.
Boarding a damaged Vulcan vessel adrift in an asteroid field, Archer and his team discover that the remaining crew have mutated into violent, zombie-like creatures. When T'Pol begins to succumb to the mutation, the crew must fight their way out before they lose her forever.
From light-years away, a powerful telepathic alien, Tarquin, mentally contacts Hoshi and convinces Archer to let the ensign briefly visit his isolated planet in exchange for crucial information on the Xindi.
After infiltrating a Xindi-Sloth plant that synthesizes vital explosive materials for the Xindi super-weapon, Archer, Reed and MACO Major Hayes capture and interrogate the plant foreman, Gralik, who upon learning of the Xindi council's attack on Earth, establishes an uneasy alliance with Archer.
After Enterprise is assaulted by severe spatial distortions, Archer loses the ability to form new, long-term memories, causing him to wake up each morning unaware that any time has passed since the day he was afflicted. Despite the crew's best efforts to keep him involved in decisions, it becomes clear over time that they can't continue to function in this manner, leading T'Pol to become his caretaker and Trip to take command of the ship.
After finding thousands of humans on a Delphic Expanse planet living in settlements seemingly straight out of the Old West, Archer gets embroiled in a dangerous cultural conflict once he discovers that the humans are systematically oppressing the alien race that originally brought them to this world.
After an accident in Engineering leaves Trip mortally injured, Dr. Phlox attempts to save the chief engineer by creating a "mimetic simbiot" ? a clone ? of him to harvest neural tissue from it. In its very short lifespan, the simbiot grows rapidly from baby to adult, and surprises the crew with detailed memories of the real Trip's life. Meanwhile, the accident has left Enterprise disabled and adrift inside a destructive space cloud, so the crew attempts to free the ship before they are stranded forever.
Ex-crewman Daniels, a temporal agent from the future, appears on Enterprise and sends Archer and T'Pol back in time to 2004 Earth, to learn why three Xindi-Reptilians have been detected in the timeline where they're not supposed to be. Using 22nd-century technology, Archer and T'Pol scour Detroit, Michigan, and locate an abandoned factory where the Xindi are developing a biological weapon with the help of a local medical worker.
A Triannon crew which Enterprise rescues from a crippled ship turns out to be a group of religious extremists who hijack the NX-01 to eradicate the "heretics" on their homeworld. Furthermore, when the group's leader, D'Jamat, learns that Archer's crew has dared desecrate the Expanse's mysterious Spheres ? which the Triannons consider holy shrines of the "chosen realm" ? he demands that Archer choose a crewman to be put to death.
Andorian Imperial Guard Commander Shran and his warship track Enterprise down in the Delphic Expanse to offer Captain Archer help as an ally, and together, the two former adversaries plan to steal a prototype of the Xindi's planet-destroying superweapon. As a confrontation with the Xindi looms, Lt. Reed gets help fixing the NX-01's damaged weapons systems from a striking Andorian female, Lt. Talas, a contentious officer with her own agenda.
Having located the prototype of the Xindi superweapon, Archer and the crew manage to capture the weapon's creator, Degra, and launch into an elaborate scheme to dupe their prisoner into revealing the location of the final weapon under construction. With time running out before the Xindi discover Degra's disappearance, the entire crew play key roles in the massive charade which combines Archer's acting skills, Trip's faux alien shuttlecraft, Hoshi's decrypted data and Dr. Phlox's memory tampering, in order to trick the Xindi scientist into believing he and Archer are now allies and on the run after escaping a Xindi-Insectoid prison.
Enterprise encounters an abnormally large spatial distortion and rescues an alien from a craft trapped inside. While Archer and Dr. Phlox try to solve the mystery behind the rapidly deteriorating alien, tensions between Lt. Reed and MACO leader Major Hayes escalate into a full-blown brawl. Meanwhile, Trip's flirtation with a female MACO forces a surprisingly jealous T'Pol to confront her attraction to her fellow senior officer.
While Enterprise travels through a section of the Expanse lethal to human neurology, Dr. Phlox must put the entire crew to sleep and handle all aspects of a working starship, but even with T'Pol's help, the doctor's skills might not be enough to keep the crew safe when complications arise. With the ship not moving out of the area fast enough, Dr. Phlox must figure out how to start the warp engines without blowing up the ship, while realizing he may not be entirely immune to the region's radiation himself.
When Enterprise stumbles upon a damaged Xindi-Insectoid ship on a barren planet, Archer and the crew search the ship and discover a cache of several dozen Insectoid eggs, but with the nursery's bio-support failing, Archer becomes fiercely determined to help his enemy's offspring hatch. As Mayweather and Tucker attempt to learn all they can about the alien ship, Archer becomes consumed with saving the Xindi hatchlings, causing the crew to start raising questions about Archer's judgment.
Enterprise finally arrives at the Xindi superweapon construction site, and despite a troubling glimpse into the future by time-traveling operative Daniels, a determined Archer leaves the ship in T'Pol's hands as he alone pilots a suicide mission to destroy the huge Earth-bound planet-killer. With Archer gone, T'Pol and the crew attempt to escape enemy territory undetected, but once discovered are forced to make a last stand against multiple Xindi attackers.
After brutally torturing Archer, the Xindi unexpectedly return him to Enterprise, which is barely holding together after a devastating Reptilian attack. The captain receives information that some possibly sympathetic Xindi Council members are willing to meet with him, but he must make a rendezvous several light-years away in just a few days. Faced with a severely crippled ship with no warp drive ? as well as numerous dead and injured crew members ? Archer tosses his ethics aside in a desperate attempt to get the ship back on its feet.
Meanwhile, T?Pol privately turns to Dr. Phlox for assistance with a disturbing secret she's been keeping for several months.
After arriving at one of the mysterious, metallic spheres for a clandestine meeting with Xindi weapon designer Degra, Archer attempts to convince the skeptical scientist and another Xindi council member that humanity isn't their enemy. Meanwhile, as the crew struggles to repair the extensive damage to Enterprise, Trip must deal with the recent death of a member of his engineering team, forcing him to also come to terms with the loss of his sister in the original Xindi attack on Earth. Also, T'Pol must confront the implications of her emotion-provoking substance addiction.
While on their way to face the Xindi Council, Archer and crew encounter a twin NX-01 manned by their own descendants, who warn that the subspace shortcut they intend to take will throw them 100 years into the past, ensuring Earth's destruction.
T'Pol and Reed lead a team on a harrowing mission into one of the mysterious metallic Spheres to obtain vital information about how the Delphic Expanse was created, as Archer and Hoshi approach the Xindi Council hoping that diplomacy can stop the launch of the superweapon aimed at Earth. Meanwhile, with Enterprise about to derail their plans to invade our universe, the transdimensional Sphere-Builders urge key members of the Xindi Council to take drastic measures to undermine the humans' peace overtures.
Archer and his new allies among the Xindi Council attempt a full-scale assault on the superweapon being deployed toward Earth by the rebellious Reptilians and Insectoids, before a kidnapped and brainwashed Hoshi can decrypt the weapon's encoded arming mechanism and unleash its devastating power. Meanwhile, T'Pol and Trip hatch a plan to destroy a Sphere which they believe will disrupt the entire network of Spheres responsible for the Expanse's spatial anomalies, bringing the transdimensional "Sphere-Builders" directly into the fray.
Aboard Degra's ship, Archer, Reed and Hoshi work with the Arboreals and Humanoids to chase the Reptilians and stop the Xindi Weapon from decimating Earth. Archer's plan is to board the weapon and try to overload the power systems, but he'll need the help of an ailing Hoshi to read the weapon schematics. Back in the Delphic Expanse, T'Pol leads the NX-01 in an attempt to obliterate Sphere 41 in hopes of disabling the entire network of Spheres. But the crew's time is limited, as that region of space has a degenerative effect on their bodies, and the furious Sphere-Builders try to tear Enterprise apart.