It primarily follows William "Skip" Sands, a newly minted CIA agent operating in Vietnam during the American insurgency.

He is following in the footsteps of his uncle, Colonel Francis Xavier Sands, a hard-drinking WWII war hero and legendary CIA operative.

Colonel Sands assigns Skip the daunting task of copying and cross-referencing a huge set of index cards containing information about people, places, and events.

The Colonel believes these cards, which he calls the Tree of Smoke, represent vital intelligence that will help the Americans win the war.

Initially, Skip believes that he will become an important part of the war effort; however, he is assigned to a remote village where he has little contact with anyone other than his two house servants.

The Colonel, with his henchman Sergeant Jimmy Storm, use their army platoon to map Vietcong tunnels in an operation known as Labyrinth.

He accuses Skip of having passed information on to Voss and their superiors at the CIA (though the real mole is Hao, who is angling to get relocated from Vietnam through any means necessary).

A nurse named Kathy who is working for a Canadian NGO is widowed at an early age when her husband, a missionary in the Philippines, is killed.

There are several references in the novel to the title phrase, which has Biblical origins in three cited passages: Song of Solomon 3:6; Book of Joel 2:30, 31; and Exodus 33:9, 10.

[4] On the November/December 2007 issue of Bookmarks, the book received rating of 4 out of 5 stars, with the critical summary saying, ""Massive," "epic," and "wildly ambitious" are the most common adjectives applied to Idaho poet and novelist Denis Johnson's latest work".

[8] Brian Reynolds Myers, in The Atlantic, wrote a highly critical review of both the book and its author, opining that "once we Americans have ushered a writer into the contemporary pantheon, we will lie to ourselves to keep him there.

"[9] In Literary Review, John Dugdale wrote: "Johnson's expertise in dialogue and atmosphere means it works on the level of the individual scene, suggesting that his natural form is the short story; but when it comes to overall structure and main plotlines, Tree of Smoke is tellingly dependent on reworking other fiction.

"[11] Kirkus Reviews stated that, with the novel, "Denis Johnson has bigger whales to land in his longest and most ambitious work to date" and that "As the novel obliterates all distinctions between good and evil, allies and enemies, loyalty and betrayal, it sustains the suspense of who will survive long enough to have the last word.

"[12] Norman Rush, in The New York Review of Books, said: "Tree of Smoke is an ambitious, long, dense, daunting novel sited at the heart of a great American evil, the Vietnam War ... Like the war itself, Tree of Smoke delivers an intense experience of loss, shame, futility, confusion—all without benefit of editorializing.