In the year 2009, Yuji Kaido is an average young adult male diagnosed with a serious disease (the "B-cells") and is put into cryogenic stasis until a cure is found. Twenty-two years later, he is awakened in the midst of a raging battle between armored soldiers and insectoid beings called the "Blue" which have overrun the Earth.
The group of soldiers are from an orbiting space colony collectively called Second Earth and were ordered to recover "sleepers" around the Earth. Among them is the soldier Marlene Angel, who at first appears to be heartless toward others. On the journey to the space colony, Second Earth,Yuji meets many of the humans that were left behind during the evacuation due to limited resources. Standing orders for Marlene and the other troops are to consider any human survivors on the surface to be already dead, which greatly troubles Yuji.
On their journey all of the soldiers are killed, except for Marlene, causing Yuji to fall into a deep depression as he recognizes the destruction around him and his own inability to save those he cares about. During their travel to Baikonur space base through the mountains, Yuji and Marlene start to develop a bond that starts to soften her sharp edges. Eventually, in Russia, Yuji and Marlene come across another group of soldiers and devise a battle plan to get back to Second Earth. During the operation to escape to Second Earth, Marlene is the last remaining pilot and completely overrun by the Blue. Just when Marlene is about to self-detonate her Armor Shrike, Yuji arrives. Determined not to leave her behind he comes to her rescue with a team of supporters (service robots). Marlene is overwhelmed at Yuji's efforts to save her. This is a turning point for Marlene and her feelings for Yuji are quite clear for the rest of the series. During the shuttle flight to Second Earth, Marlene and Yuji expose their emotions for each other. Marlene and Yuji's scene is abruptly interrupted as a mutated Blue which hid in the shuttle attacks Yuji, critically injuring him.
Upon arrival, Marlene and Yuji are separated, and Marlene is sent back into training at the education station. Not knowing what happened after he was attacked, Marlene rebels and is bent on finding Yuji. When she does, she finds he is healed and being trained to use a new specialized "sleeper"-specific Armor Shrike (A.S) called the "Double Edge", a battlesuit that is much stronger than the originals used in war against the Blue. It is discovered the illness that Yuji is afflicted with is the key to help destroying the Blue and taking back the planet. He, and other "Sleepers", have "B-cells" which are also the genetic make up of the Blue.
After intensive training, Yuji and Marlene return to Earth with two other "Sleepers" named Tony Frost and Alicia Whistle. Tony is an inexperienced A.S pilot, but his B-cells are very adept, giving him great A.S skills. Alicia is only a young teenager with no combat experience and not much sense as to what is going on around her. They and the other forces of Second Earth battle the Blue. They become successful at destroying a few of the largest nests before they head back to Second Earth. However, the battles begin to have a negative effect on Yuji who gives very little regard for human life and is completely obsessed with being better than Tony at killing Blue. Yuji's actions deeply concerns Marlene and she begins to know something is wrong.
Shortly after returning to Second Earth, the High Council orders the "Sleepers" on a second offensive against the Blue. Marlene is separated from Yuji once again, but in his current state he does not seem to care. As the "Sleepers" are carrying out their mission, a battle on Second Earth between two factions is waged. Seno, the head of Second Earth's science division, leads the "Ark" rebellion taking control of the military, lunar resource, and education stations of Second Earth. The High Council escapes to and retains control of the medical station. During this time Marlene learns about the nature of the illness that put Yuji in stasis, the source of his abilities, and the source of the Blue Insectoids. They are a defense mechanism enacted by the Earth to purge the existence of humanity, and the B-cells that exist in the "Sleepers" could become a potential threat to humanity as well.
After the "Ark" successfully takes over Second earth from the ignorant High Council, Marlene heads down to earth in search of Yuji. When she finds him his B-cells are already beginning to activate and he begins to go berserk as a killing machine. After struggling and fighting with him, Marlene is finally able to get through to Yuji and helps him overcome his madness by showing her human emotions and feelings for him (this is ironic because in the beginning of the series Marlene is the brutal military soldier and it is Yuji uses his emotions to help Marlene realize her human sensitivity). Meanwhile, Tony and an unknowing Alicia have also abandoned the remaining grounds forces. The troops fend off waves of Blue before escaping with the few remaining survivors. Tony and a now brainwashed Alicia also eventually return to Second Earth, but bring with them several Blue when they board the medical station.
When Yuji and Marlene return to Second Earth, they find that Tony plans to ram the medical station into the military station, which would therefore destroy the heart of Second Earth. He sees this as the "Grand Will of the Earth", in which he will become a "messiah" and cleanse the planet of humanity forever. However, Yuji, Marlene, and a group of other soldiers infiltrate the station, and manage to free Alicia's mind after injuring her. Later, Yuji and Marlene confront and eliminate Tony, while Rick (a close friend and partner to Yuji and Marlene) is slaughtered by a Blue. Alicia ventures back to Tony to die with him as the military destroys the medical station.
After the decision by Seno's junta to abandon Earth, Yuji becomes depressed and contemplates his existence, wondering what he has been fighting for, why he was woken, why he cannot save his friends (Joey near the beginning, Tony from his madness, and Alicia from Tony's brainwashing), and what is truly Earth's will. However, Marlene again is able to get through to Yuji and the two realize they need each other and finally become lovers.
Yuji decides to return to Earth to once and for all find out what Earth's Will is. After learning from Seno about a new migration pattern of the Blue, Yuji and Marlene take a group of volunteers and head to an area where a massive nest is located. There they find a group of humans who seem to be surviving in the area. The nest seems impenetrable at first, but they eventually find an entrance with the help of the local people.
The entrance leads to a tunnel where the walls, ceiling, and floor of the cavern are composed of fossil-like Blue. The team finally comes upon a crystal formation in a massive cavern. A huge Blue is birthed from the gel substance sitting atop the formation and kills everyone except for Yuji and Marlene. Yuji kills it and comes to the conclusion that the sphere will hold the answers he seeks. He sends Marlene, who is pregnant with their child, away to the surface to wait for him. He then gets a vision and can see what the earth itself can see. Yuji comes to understand how mankind can live alongside the B-Cells and returns to Marlene.
Meanwhile, Second Earth's military station's citizens revolt against Seno. The station's personnel proceed to abandon the station for Earth via shuttles. Eventually a firefight erupts over the last remaining overcrowded shuttle, and the station is destroyed by a massive explosion. All around the world from former Blue Nests, long strings of coalescing energy ascend into Earth's atmosphere and form a ring. Marlene and Yuji watch this, realizing Earth is now a safe place to be and look forward to the rest of their lives together as the sun sets. A final view of the Earth from space is shown with a slightly garbled narration, presumably by the Earth, stating, "Welcome to the other realm, this is your journey".