In 1886, Doyle finished the first Sherlock Holmes novella, A Study in Scarlet. After several rejections, he was forced to sell it outright for £25 for inclusion in the 1887 Beeton's Christmas Annual, a holiday collection that often sold out, but did not usually attract much attention in the national press. The work was reprinted in 1889 and many more times, but Conan Doyle never earned another penny from it. Sign of the Four, the second work to feature Holmes and Watson, also achieved a small, but by no means brilliant, success.

Arthur Conan Doyle in 1891, the year Holmes made him a celebrity

While writing the early Holmes stories, Doyle also began what he considered his most important work: chivalric, historical novels based on British history, primarily, Micah Clark, Sir Nigel, and The White Company. Although these novels were widely admired, none of them created the stir caused by the first series of short stories featuring Sherlock Holmes and John Watson that appeared in The Strand Magazine, starting in 1891. Despite their overwhelming success, Conan Doyle never suspected that these stories would be the foundation of his literary legacy.

After writing three series of twelve Holmes stories, receiving the unheard-of sum of £1000 for the last dozen, Conan Doyle was sick to death of the popular detective and decided to kill him off in the 1893 story, "The Final Problem." Conan Doyle considered the Holmes stories light fiction, good for earning money, but destined to be quickly forgotten, the literary equivalent of junk food. "I couldn't revive him if I would, at least not for years," he wrote to a friend who urged Holmes's resurrection, "for I have had such an overdose of him that I feel towards him as I do towards pâté de foie gras, of which I once ate too much, so that the name of it gives me a sickly feeling to this day." The vehement public reaction to Holmes's death must have shocked Conan Doyle. People wore black armbands and wrote him pleading—or threatening—letters. Still, it was nine years before he capitulated to public opinion and brought Holmes back.

The third Holmes novel, The Hound of the Baskervilles, appeared in nine parts in The Strand Magazine during 1901-2, but it was presented as an old case from Watson's records, completed before Holmes's death. Conan Doyle did not make up his mind to resurrect Holmes until 1903, when he wrote "The Empty House." He continued, reluctantly, to produce Holmes stories until 1927, three years before his own death.

Conan Doyle became an important public figure, twice standing (unsuccessfully) for Parliament. He was knighted for his efforts on behalf of the Boer War, both as the author of a persuasive, pro-war book and as a volunteer, caring for wounded British soldiers in the field. He even took on several real-life mysteries, using Holmes's methods and his own status as a famous author to free two unjustly imprisoned men.

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