There is talk of war stirring back home between authorities and multiple anti-technology factions opposed to this kind of genetic engineering, including a terrorist group or radical movement known as "non ultra natura" (nothing greater than nature).

Dr. Kern is left stranded in orbit awaiting rescue, periodically waking from stasis, and she is troubled by the sudden cessation of radio signals bleeding out from humanity's home.

Faced with the slow collapse of Earth's biosphere due to the long-delayed consequences of the ancient war, the last remnants of humanity are en route to Kern's World aboard the starship Gilgamesh, hoping for a paradisiacal planet and ignorant of the uplifted Portiid spiders.

Confronting Dr. Kern, who is powerful and rendered crazed and xenophobic by the millennia, in orbit, the Gilgamesh takes a centuries-long detour to a neighboring system that proves uninhabitable.

The novel plays off the contrast between the rapid advancement of the spiders' societies and the descent of the crew of last humans into strife and barbarism, primarily seen through the eyes of the Gilgamesh's chief classicist, Holsten Mason.

Guyen leads the ark ship to another terraformed world after Kern forces his hand and discovers experimental Old Empire technology capable of uploading a human mind to a sufficiently complex computer.

He eventually devotes himself to a new quixotic purpose: uploading his mind to the Gilgamesh computer, as a means of establishing firmer control over the ship itself before returning to Kern's World.

The Gilgamesh chief engineer and its eventual de facto leader, Lain is frequently forced to hold the ark ship together in the face of near-insurmountable mechanical breakdown.

Sacrificing decades of her life guiding and preserving “the tribe”—primarily descendants of engineering; initially, Lain's anti-Guyen faction—and the vessel itself, she becomes the spiritual leader of Gilgamesh's ship-born generations.

The spiders each have their own identities, lives, and experiences, on top of their genetic memories called "Understandings," although the narrative refers to its main and supporting characters by four different names based on distinct personalities or historical archetypes.