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Over 75 years ago the spaceship Conestoga left Earth on a nine-year one-way mission to establish the first human colony outside the solar system, called Terra Nova. The colony thrived on their beautiful new planet, and was such a success the Space Agency on Earth decided to send another vessel. The colonists protested and angry messages were traded, then one day all transmissions from Terra Nova ceased. Decades later the Warp 5-capable Enterprise NX-01 is dispatched to find out what happened to that lost colony.

After the ship enters orbit over Terra Nova, Captain Archer's hails go unanswered and scans show no bio-signs, but low levels of mysterious radiation are detected. Archer leads an away team to the surface and finds the colony structures deserted and rusting. T'Pol determines that the radiation levels 70 years ago would have been lethal, but no bodies are found. But then Lt. Reed detects a humanoid moving through the forest, and the away team tracks the figure to the mouth of a network of caverns. Archer and Reed go in to explore and encounter a society of cave dwellers wearing scaly body armor. Attempts at friendly communication are met with gunfire, and Reed takes a bullet in the thigh. Archer has no choice but to escape the barrage and retreat with the other crewmen, leaving Reed behind. While they take off in the shuttlepod, T'Pol's scans indicate the attackers are human.

Back on Enterprise, new scans reveal 52 bio-signs underground, all human, but right now Archer is only interested in the injured Reed. As they examine the cavern geology to plan a rescue, Archer and T'Pol conjecture that the cave dwellers are descendents of the original colonists, driven underground by the radiation. Archer takes Dr. Phlox with him back to the surface and they let themselves be captured. The cave dwellers speak to them in an odd dialect of English, calling themselves Novans. The aged Jamin and his sickly mother Nadet express their resentment toward humans, whom they blame for the "poison rain" many years ago. Archer tries to convince the Novans that they're descended from humans, and wants to help them determine the true cause of the radiation. And after Phlox diagnoses Nadet with lung cancer, Archer offers to treat her aboard his "sky ship." Jamin consents, on the condition that Reed stay behind despite his injury, and he and Nadet ride the shuttlepod with Archer and Phlox to Enterprise.

Although Nadet is a troublesome patient, Phlox is able to determine a treatment for her. While he synthesizes medicine, Archer shows the guests archived pictures from the early days of the Terra Nova colony, but Jamin accuses Archer of lying and trying to confuse them. Meanwhile T'Pol discovers an impact crater on the surface indicating that an asteroid collision caused a radioactive cloud about 70 years ago that enveloped the northern hemisphere where the colony was located. Also, ensigns Sato and Mayweather unearth from the colony's communications tower a transmission still in the data buffer, from a colony leader accusing Earth of making an attack.

Archer surmises that only the colony's young children survived the radiation and began living underground, and their last memories were of their parents blaming humans for destroying the colony. Dr. Phlox then informs Archer that the Novans are suffering from micro-cellular decay caused by contaminated groundwater, which he cannot treat. Archer attempts to explain the situation to the Jamin and Nadet and convince them the Novans need to leave the planet and come to Earth. They are resistant and accusatory as usual, so Archer shows Nadet another archived photo that he found, one that includes her mother and herself as a child. It sparks her memory, but Jamin insists on returning to the surface, threatening that Reed will be "gutted" if they are not back before daybreak. Since Archer refuses to take the Novans by force, T'Pol offers an alternative that won't destroy their unique culture: relocate them to the southern hemisphere, which is unaffected by the asteroid. On the shuttlepod ride back, Archer appeals to Jamin and Nadet to consider that proposal and talk to their people about it.

When the shuttlepod lands, the ground collapses beneath them and they fall into the underground caverns. They escape the shuttle unhurt, and Jamin sets out to guide Archer back to where Reed is, but then they hear the cries of a Novan man who has become trapped by a large fallen root in a deep pit rapidly filling with water. In order to save him, Jamin and Archer have to work together, and Jamin decides to trust Archer to use his phase-pistol to cut the root in half so they can pry it off the injured man. Later, though, it is Nadet who appeals to the other Novans to listen to the humans, finally acknowledging that she was the little girl in that picture and that she is herself human. After the Enterprise crew helps the Novans relocate, thus saving them from extinction, Archer gives Mayweather the honor of writing the report for Starfleet describing how the Terra Nova puzzle was solved at last.