Implicitly set in the early 1990s, Ishmael begins with a newspaper advertisement: "Teacher seeks pupil. Must have an earnest desire to save the world. Apply in person". The nameless narrator and protagonist thus begins his story, telling how he first reacted to this ad with scorn because of the absurdity of "wanting to save the world", a notion he feels that once he naïvely embraced himself as an adolescent during the counterculture movement of the 1960s. Feeling he must discover the ad's publisher, he follows its address, surprisingly finding himself in a room with a live gorilla. On the wall is a sign with a double meaning: "With man gone, will there be hope for gorilla?" Suddenly, the gorilla, calling himself Ishmael, begins communicating to the man telepathically. At first baffled by this, the man learns the story of how the gorilla came to be here and soon accepts Ishmael as his teacher, regularly returning to Ishmael's office. The novel continues from this point mainly as a dialogue between Ishmael and his new student.
Ishmael's life began in the African wilderness, though he was captured at a young age and has lived mostly in a zoo and a menagerie (before living permanently in a private residence), which caused Ishmael to start thinking about ideas that he never would have in the wild, including self-awareness, human language and culture, and what he refers to as the subject he specifically teaches: "captivity". The narrator admits to Ishmael that he has a vague notion of living in some sort of cultural captivity and being lied to in some way by society, but he cannot articulate these feelings fully.
The man frequently visits Ishmael over the next several weeks, and Ishmael proceeds to use the Socratic method to deduce with the man what "origin story" and other "myths" modern civilization subscribes to. Before proceeding, Ishmael lays down some basic definitions for his student:
- A story is an interrelation between the gods, humans, and the earth—with a beginning, middle, and end.
- To enact is to behave in such a way to make a story (however true or not) come true.
- A culture is a people who are enacting a story.
- Takers are "civilized" people, particularly, members of the culture that first emerged in an Agricultural Revolution starting 10,000 years ago in the Near East that has developed into today's globalized society (the culture of Ishmael's pupil and, presumably, the reader).
- Leavers are people of all other non-civilized cultures existing in the past and the present; often derogatorily referred to by Takers as "primitive".
At first, the narrator is certain that civilized people no longer believe in any "myths", but Ishmael proceeds to gradually tease from him several hidden but widely accepted premises of "mythical" thinking being enacted by the Takers:
- Humans (especially Takers) are the pinnacle of evolution.
- The world was made for humans, and humans are thus destined to conquer and rule the world.
- This conquest is meant to bring about a paradise, as humans increase their mastery over controlling nature.
- However, humans are always failing in this conquest because they are flawed beings, who are unable to ever obtain the knowledge of how to live best.
- Therefore, however hard humans labor to save the world, they are just going to go on defiling and destroying it.
- Even so, civilization—the great human project of trying to control the whole world—must continue, or else humans will go extinct.
Ishmael points out to his student that when the Takers decided all of this, especially the idea that there is something fundamentally wrong with humans, they took as evidence only their own particular culture's history: "They were looking at a half of one percent of the evidence taken from a single culture. Not a reasonable sample on which to base such a sweeping conclusion". On the contrary, Ishmael asserts that there is nothing inherently wrong with humans and that a story that places humans in harmony with the world will cause humans to enact this harmony, while a destructive story such as this will cause humans to destroy the world, as humans are doing now. Ishmael goes on to help his student discover that, contrary to this Taker world-view, there is indeed knowledge of how humans should live: biological "laws" that life is subject to, discernible by studying the ecological patterns of other living things. Together, Ishmael and his student identify one set of survival strategies that appear to be true for all species (later dubbed the "law of limited competition"): in short, as a species, "you may compete to the full extent of your capabilities, but you may not hunt down competitors or destroy their food or deny them access to food. In other words, you may compete but you may not wage war". All species inevitably follow this law, or as a consequence go extinct; the Takers, however, believe themselves to be exempt from this law and flout it at every point, which is therefore rapidly leading humanity towards extinction.
To illustrate his philosophy, Ishmael proposes a revision to the Christian myth of the Fall of Man. Ishmael's version of why the fruit was forbidden to Adam and Eve in the Garden of Eden is: eating the fruit of the Tree of the Knowledge of Good and Evil provides gods with the knowledge of who shall live and who shall die—knowledge which they need to rule the world. The fruit nourishes only the gods, though. If Adam ("humanity") were to eat from this tree, he might think that he gained the gods' wisdom (without this actually happening) and consequently destroy the world and himself through his arrogance. Ishmael makes the point that the myth of the Fall, which the Takers have adopted as their own, was in fact developed by Leavers to explain the origin of the Takers. If it were of Taker origin, the story would be of liberating progress instead of a sinful fall.
Ishmael and his student go on to discuss how, for the ancient herders among whom the tale originated, the Biblical story of Cain killing Abel symbolizes the Leaver being killed off and their lands taken so that it could be put under cultivation. These ancient herders realized that the Takers were acting as if they were gods themselves, with all the wisdom of what is good and evil and how to rule the world: agriculture is, in fact, an attempt to more greatly create and control life, a power that only gods can hold, not humans. To begin discerning the Leavers' story, Ishmael proposes to his student a hypothesis: the Takers' Agricultural Revolution was a revolution in trying to strenuously and destructively live above the laws of nature, against the Leavers' more ecologically peaceful story of living by the laws of nature.
The Takers, by practicing their uniquely envisioned form of agriculture (dubbed by Quinn "totalitarian agriculture" in a later book) produce enormous food surpluses, which consequently yields an ever-increasing population, which itself is leading to ecological imbalances and catastrophes around the world. Ishmael finishes his education with the student by saying that, in order for humanity to survive, Takers must relinquish their arrogant vision in favor of the Leaver humility in knowing that they do not possess any god-like knowledge of some "one right way to live". Ishmael tells his student to teach a hundred people what he has learned, who can each pass this learning on to another hundred.
The student becomes busy at work, later discovering that Ishmael has fallen ill and died of pneumonia. Returning to Ishmael's room one day, he collects Ishmael's belongings. Among them he discovers that the sign he saw before ("With man gone, will there be hope for gorilla?") has a backside with another message: "With gorilla gone, will there be hope for man?"