Preface
The author explains to his readers that since the publication of his autobiography will happen after he is dead, he is "speaking from the grave,'' and so will not have to censor himself.

Chapters 1-17
Clemens is born in the small village of Florida, Missouri. He remembers an uncle whom he admired, and describes this uncle's general store and the farm where Clemens stayed for a few months each year. Clemens says that he could never be totally equal with his Negro friends on the farm, due to their differences in skin color and social stature.

He recalls his mother and father, and explores his ancestral connection to Geoffrey Clement, who helped to sentence England's King Charles I to death. Clemens describes his father's purchase of 100,000 acres of then-worthless Tennessee land and the family's move to Hannibal, Missouri. He remembers his mother's death, and discusses her infinite compassion.

Clemens is a troublemaker and has problems at both school and home. As a teenager, he gets into more precarious situations. He fakes a trance for a hypnotist to get the approval of the audience, and has to act like it does not hurt when they stick him with pins. He reflects on various friends from his boyhood who have contacted him as an adult, then introduces his brother Orion.

Chapters 18-28
Clemens' s father dies in 1847, sending the family into poverty. Clemens becomes a printer's apprentice, then works for his brother Orion's newspaper. Orion is so honest that he lowers prices too far to make a profit, a trend he continues with other businesses.

Clemens decides to travel to South America, then becomes a riverboat pilot instead. In a dream, he predicts his brother Henry's upcoming death. He then joins the Confederate army for two weeks while in Louisiana.

Through a personal connection, Orion becomes secretary of the new territory of Nevada. Clemens moves to Nevada with him, and starts writing for the Virginia City Enterprise, eventually adopting his pseudonym Mark Twain a nautical term meaning two fathoms (twelve feet). When Twain's editor is out of town, Twain is challenged to a duel in the editor's place. The man who challenged Twain to a duel is scared away after one of the other men from the newspaper office creates a lie about Twain's marksmanship.

When Twain moves to San Francisco, he becomes the only reporter on the Morning Call. He covers the courts and the theaters, and creates news when there is not any. The editor hires an assistant to help Twain, and the assistant ends up doing Twain's job to the point where Twain gets fired.

Twain meets Bret Harte, a writer who becomes famous for a style of literature that mimics Dickens. Twain explains how Harte's character changed from honest to dishonest when Harte moved from San Francisco to the East.

Twain is sent by the Sacramento Union to the Sandwich Islands, where he writes about the survivors of a boat accident. Back in the United States, he begins a lecture tour as a result of his growing fame.

Chapters 29-35
Twain takes a trip around the world, then writes The Innocents Abroad based on his experiences. The book is a rousing success, but Twain gets swindled out of some of his royalties because he is uneducated about the publishing business.

Twain remembers his first lecturing experience and how he got on the national lecturing circuit through James Redpath's bureau in Boston. Twain lectures for three seasons, then retires to his married life.

Chapters 36-42
Twain discusses his courtship of and marriage to Olivia L. Langdon, an invalid most of her life, who denies Twain's proposals several times before agreeing to marry him. Twain's first child, Langdon, dies from complications due to a cold. His second child, Susy, is an inquisitive and passionate child who troubles over the meaning of human existence and who exhibits a mature sense of fairness. She undertakes a frank biography of her father when she is thirteen years old.

Chapters 43-52
While in San Francisco, Twain gets two potential opportunities from an investor, both of which are foiled inadvertently by Twain's brother Orion. Twain does not make much money on his next several books or investments, and decides to become his own publisher. He puts his nephew-in-law, Webster, in charge of the business, starting with the publication of Twain's The Adventures of Huckleberry Finn.

Twain receives the contract to publish the memoirs of his friend General Grant, and reflects on his past experiences with this former President and Civil War hero. Grant's book is a success, and it earns his heirs about half a million dollars.

Webster renegotiates his contract with Twain a couple of times, cheating Twain out of money and decision-making rights in the process. Twain buys out Webster, but Webster's mismanagement bankrupts the business. Twain reimburses his creditors by liquidating the company's assets and earning the rest himself through another lecture tour and the publication of his book Following the Equator.

Chapters 53-60
Twain discusses his half-completed books, his laziness, and his newfound dependence on dictation. He reflects on the other humorists from his early career, most of whom have become unknowns by this time. He expresses his views about the ignorance of copyright laws and the ignorance of inexperienced writers who try to get published. Twain relates how he unknowingly met his favorite author Rudyard Kipling before the writer became famous, then talks about authors who have fame with the lower classes.

Chapters 61-64
Twain talks about his increasing disdain for Bret Harte, who has angered creditors, critics, and friends with irresponsible behavior. Twain notes that Harte can only write when the pressure from creditors is strongest, then discusses how Harte has abandoned his family, including trying to figuratively stab his son in the back.

Twain pardons Harte's actions, saying he is like other creatures of nature, using God-given traits, whether good or bad. Twain talks about trickery in general, and gives examples of tricks that have been played on others.

Chapters 65-71
Twain relates the details of the death of his daughter Susy, who contracts meningitis while Twain is abroad in England. He then discusses the death of his wife, resulting from the failure of her immune system.

Twain writes that, during his wife's final months, their daughter Jean caught a chill and got double pneumonia. The family hides Jean's illness from Twain's wife through Twain's daughter Clara, who lies to her mother about Jean—the first time Clara has ever lied to her mother. Twain moves his wife back to their villa, where she dies.

Chapters 72-78
Twain shares his negative views on Europe, then jumps at the chance to travel there to receive an honorary degree from Oxford. During his trip, an acquaintance tricks him into lunching with her so that she can parade him around through carefully staged events designed to improve her reputation with the press.

Twain meets with an English author who has recently gained notoriety for her salacious novel, which Twain praises privately but says he can never defend publicly. Twain attends the overly elaborate memorial dedication for a writer friend, whose wife is preoccupied with her reputation. He talks about his reputation for not following common superstitions.

Chapter 79
Twain describes his daughter Jean's death from heart failure caused by an epileptic seizure, then remembers back on other loved ones he has lost— Susy, his wife, friends—and reflects on the fact that he is alone until he dies. He describes death as a gift.