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The first novel by Frank Herbert sets the year as 10,190 After Guild; a period in our distant future at a time where much historical knowledge of humanity's past has been lost, although some cultural and religious traditions remain. The calendar used in this time is not the same as the Gregorian calendar system, so it is difficult, or impossible, to identify just how far in the future the events described take place.

The main conflict driving the narrative of Dune is a political struggle among three noble houses: House Atreides, House Harkonnen, and the Imperial House Corrino. The Corrino Emperor, Shaddam IV, has come to fear the Atreides, in part because of the popularity of Duke Leto Atreides (Shaddam's cousin and the leader of House Atreides) with the noble houses of the Imperium, represented in the Landsraad assembly. In addition, the Duke and his talented lieutenants, Duncan Idaho, Gurney Halleck and Mentat-assassin Thufir Hawat, are making the fighting force of House Atreides equal in effectiveness to the dreaded Imperial Sardaukar, although they are much fewer in number. The Emperor decides that House Atreides must be destroyed, but he cannot risk an overt attack on a single House; to do so would by necessity unite the other houses against him in an all out Galactic War. Instead, Shaddam uses the centuries-old feud between House Atreides and House Harkonnen to disguise his assault, enlisting the brilliant and power-hungry Baron Vladimir Harkonnen in a plan to eliminate the man he fears.

The Atreides are forced to accept the lucrative fief of the desert planet Arrakis, also known as "Dune," replacing the Harkonnens. Dune is the only known source of the spice melange, the most valuable commodity in the universe: it is needed by the navigators of the Spacing Guild for interstellar travel; it is used by the secretive and powerful Bene Gesserit sisterhood to awaken the genetic memories of their ancestors; and it greatly extends the human lifespan and expands awareness. Without spice production, all interstellar activity would cease, and the Landsraad, the federation of Great Houses, would crumble.

Complicating the political intrigue is the fact that both Paul Atreides, the Duke's son, and Feyd-Rautha Harkonnen, the Baron's nephew and heir, are essential parts of the Bene Gesserit's secret, centuries-old breeding program to create a prescient superhuman — and male equivalent to a Bene Gesserit — called the Kwisatz Haderach. The Bene Gesserit had planned to breed an Atreides daughter with Feyd-Rautha to unite the two bloodlines and produce their long-awaited prize. But instead of bearing a daughter as ordered, the Lady Jessica fulfilled her beloved Duke's wishes for a son and bore Paul. This was a tremendous setback for the breeding program, as the Bene Gesserit knew of the Emperor's plans to destroy House Atreides, putting their most valued bloodlines in great jeopardy, just as they were so close to reaching their goal. Further, there were signs that Paul might actually be the Kwisatz Haderach, born one generation earlier than expected. (This may have been literary foreshadowing, in that Kwisatz Haderach means "Shortening of the Way".) The prospect of a rogue Kwisatz Haderach beyond Bene Gesserit control was terrifying to the Sisterhood.

The transfer of control of Arrakis creates another pretext for conflict between the Harkonnens and the Atreides and removes Duke Leto from his power base on his home world of Caladan. While they anticipate a trap, the Atreides are unable to withstand a devastating Harkonnen attack, supported by Imperial Sardaukar disguised as Harkonnen troops and aided by a traitor within House Atreides itself, the Suk doctor, Wellington Yueh.

Captured, Duke Leto dies in a failed attempt to assassinate the Baron Vladimir Harkonnen using a poison gas capsule planted in a fake tooth by Dr. Yueh, but Paul and Jessica escape into the deep desert. With Jessica's Bene Gesserit abilities and Paul's developing skills, they manage to join a band of native Fremen, ferocious fighters who ride the giant sandworms that dominate the desert planet. Paul emerges as the Kwisatz Haderach, and Jessica's knowledge of the secret religious myths of the Fremen, planted by the Bene Gesserit Missionaria Protectiva long ago, enable him to become acknowledged as the Lisan al-Gaib, the religious and political leader the Fremen have been waiting for. Paul unites millions of the Fremen into an unstoppable military force, including the Fedaykin.

Paul seizes control of Arrakis and the spice, defeating the Sardaukar legions Shaddam had brought to Arrakis and avenging his family in a duel to the death with Feyd-Rautha. He forces Shaddam to abdicate and becomes Emperor in his place, establishing an Atreides dynasty.