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The novel is largely set in and near the town of Dillsborough, in the fictional Rufford County. The two principal subplots center on the courtship behaviour of two young women. The heroine, Mary Masters, is the daughter of an attorney, and has been raised as a gentlewoman. Her stepmother is from a lower social order; believing it best for Mary, she pressures her strongly to accept a proposal from Lawrence Twentyman, a prosperous young yeoman farmer with aspirations to gentility. While Mary respects Twentyman for his excellent qualities, she feels that she cannot love him as a wife should a husband. She admires Reginald Morton, whose cousin is the squire of Bragton and thus one of the two major landowners of Rufford County. Reginald admires Mary as well; but for most of the novel, each is ignorant of the other's feelings: Mary, as a gentlewoman, cannot take the initiative in such a matter; and Reginald, misinformed that Mary loves another, is unwilling to make an offer and have it rejected. The anti-heroine of the novel is Arabella Trefoil. Her father is cousin to the Duke of Mayfair; her mother was a banker's daughter. Her parents are unofficially separated, and living in straitened circumstances. Arabella and her mother, Lady Augustus Trefoil, have no fixed abode; they wander from place to place, visiting people who cannot refuse them without creating social awkwardness. At Lady Augustus's direction, Arabella has spent many years struggling to secure a rich husband who will give her and her mother high social standing, an assured income, and a house of their own. She has lately become provisionally engaged to John Morton, the squire of Bragton and a rising figure in the Foreign Office. He would be an adequate but not outstanding husband by her standards; and when the opportunity presents itself, she attempts to entrap the wealthy and titled young Lord Rufford, concealing these attempts from Morton so that she can accept his proposal should they fail. John Morton falls ill and dies. Arabella, who is not altogether wicked, visits him at his deathbed despite the fact that this will assist Lord Rufford in escaping her toils. After Morton's death, she accepts an offer of marriage from Mounser Green, a Foreign Office clerk who is taking Morton's place as ambassador-designate to Patagonia. Like Morton, Green is not a brilliant match for her, but an acceptable one. John Morton's death makes Reginald Morton the squire of Bragton; at this point, when Mary Masters fears that he has moved too far above her in status, he confesses his love to her. A proposal ensues and is eagerly accepted. The American senator of the title is Elias Gotobed, who sits in the US Senate for the fictional state of Mikewa. The guest of John Morton, Senator Gotobed is trying to learn about England and the English. Through his often-tactless remarks in conversation, through his letters to a friend in America, and through a lecture in London titled "The Irrationality of Englishmen", he comments on British justice and government, the Church of England, the custom of primogeniture, and other aspects of English life.

Barchester Towers, published in 1857, is the second novel in Anthony Trollope's series known as the "Chronicles of Barsetshire". Among other things it satirises the then raging antipathy in the Church of England between High Church and Evangelical adherents. Trollope began writing this book in 1855. He wrote constantly, and made himself a writing-desk so he could continue writing while travelling by train. "Pray know that when a man begins writing a book he never gives over," he wrote in a letter during this period. "The evil with which he is beset is as inveterate as drinking - as exciting as gambling." And, years later in his autobiography, he observed "In the writing of Barchester Towers I took great delight. The bishop and Mrs. Proudie were very real to me, as were also the troubles of the archdeacon and the loves of Mr. Slope." But when he submitted his finished work, his publisher, William Longman, initially turned it down, finding much of it to be full of "vulgarity and exaggeration". More recent critics offer a more sanguine opinion. "Barchester Towers is many readers' favourite Trollope", wrote The Guardian, which included it in its list of "1000 novels everyone must read"