It is 1959, and missionary Nathan Price moves his family from Bethlehem, Georgia to the Belgian Congo in Africa.  He and Orleanna have four daughters: Rachel is the oldest at 16; Leah and Adah are intellectually-gifted twins, aged 14;  Leah idolizes her father, while Adah (who walks with a limp and doesn't speak) has a poetic eye with a love for palindromes; the youngest daughter, Ruth May, is five.  The mother and four daughters take turns narrating the story from their different points of view.

Nathan is a stubborn man; he feels he is always right, and his Baptist preaching never takes account of the beliefs of the Congolese or the reality of their new environment.   He tries to grow a garden as they would back home, ignoring local advice, but it gets washed away in the heavy rains.  Nathan doesn’t understand that the reason none of the Congolese will agree to be baptized is because the river is infested with man-eating crocodiles.  The local schoolmaster, Anatole, tries to explain the culture to the Prices.  Nathan insults him, but Anatole sends a boy (Nelson) over to help out anyway.  Ruth May, who enjoys hanging out in trees, falls and breaks her arm.  When Nathan flies her to a Belgian doctor, he is angered by the doctor's opinion that Nathan's "civilization" might not be what the Africans need.   Adah is miraculously saved from being eaten by a lion, an event which Nathan capitalizes on to attract more churchgoers.   

A year goes by.  The Underwoods, another missionary couple, warn the Prices that the Congo is going to be granted independence from Belgium and they should leave, but Nathan won’t let them.  He takes Leah with him to the capital, Leopoldville, and they watch Patrice Lumumba be sworn in as Prime Minister.  (Soon afterwards, Lumumba asks for American aide but is refused; when he seeks help from the Soviet Union, Westerners begin to turn against him.)  While they are gone, Orleanna falls into a depression and Ruth May seems to follow her.  After Rachel struggles to be the "mother" of the group, Orleanna finally gets out of bed.  With Congolese independence, most missionaries return to their home countries, and funds and supplies are drastically reduced for the Price family.  Despite hardships and his family's longing to go home, Nathan declares they will stay.

They are visited by Brother Fowles, the former missonary of the village, along with his African wife and their children.  Fowles's willingness to merge his beliefs with the spirituality of the villagers infuriates Nathan.   Next, the chief of the village wants to marry Rachel, but the Prices foil his plan by pretending she’s engaged to Axelroot, a shady pilot who brings supplies and mail.  Rachel is at first disgusted by him, but her feelings become complicated.  They realize that Ruth May has malaria, and discover she hasn't been taking her medicine.  Anatole lets Leah teach at his school, and with Nelson shows her how to hunt.  The village is invaded by ants and everyone rushes to the river, almost killing Adah.  Leah tells Anatole that she loves him, but he tries to put her off.

Prime Minister Lumumba is overthrown, arrested and tortured by Joseph Mobutu, an army officer with the covert backing of the USA and Belgium.   Meanwhile, the villagers hold an "election" on whether to accept Jesus or not.  Jesus "loses". Snakes start to appear in the Prices' chicken coop.  The children spread ashes on the ground around it to identify the person putting the snakes there.  The next morning, Ruth May dies from a snake bite; the ashes reveal the culprit to be the village medicine man.  On the same day, Lumumba is killed on the orders of Mobutu, with Belgian and CIA assistance.  (Mobutu will rename the country Zaire and his dictatorship will endure for the next three decades.)

In the wake of Ruth May's death, Orleanna silently leads her daughters out of Kilanga, leaving Nathan behind. They walk along the road in torrential rain as far as Bulungu, but then Leah falls too ill with malaria to continue. From Bulungu, Rachel is flown to Johannesburg by Eeben Axelroot (she pretends to be his wife -- the first of several "husbands" for Rachel), and Adah and Orleanna make their way to the Belgian embassy in Leopoldville, and then on to Georgia. As Leah convalesces under Anatole's care, they fall in love with each other, and she decides to remain in the Congo as his wife.

The decades go by swiftly; daughters and mother remain mostly apart as the 1960s turn into the 70s and 80s.  Rachel marries and divorces twice, and is finally widowed after her third husband dies, leaving her a resort hotel in the neighboring French Congo.  Though it is not the American life she once dreamt of, she finds her calling and a new happiness in the relative wealth of her estate. Leah, on the other hand, decides to stay in the abject poverty of Zaire, where she and Anatole have four children. After Anatole is imprisoned multiple times, they end up on a communal farm in Angola where they fight for African freedom. Adah dedicates her life to science and becomes a doctor in Atlanta; after completely overcoming her handicaps, she ends up studying viruses in Atlanta. Orleanna moves to Sanderling Island, Georgia, where she lives in retirement, thinking often of Africa and hoping for forgiveness from the child she lost.  Nathan becomes a jungle recluse but still attempts to convert Africans; he is eventually killed by angry villagers after being blamed for an accident.  

The final section, “The Eyes in the Trees,” is told in the omniscient voice of Ruth May as she watches her sisters and mother return for one final trip to Africa. They want to put a tombstone on her grave, but learn that the village of Kilanga no longer exists. The novel ends as Ruth May offers final forgiveness to her mother and a posthumous reflection on the nature of life and death.

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