Lord of Misrule is set in West Virginia on a fictional, lower-class racing track called Indian Mound Downs. At this racetrack, run-down, second-grade horses are frequently raced, bought and sold. Tommy Hansel and his girlfriend Maggie Koderer come into town with four horses that, on paper, look like losing bets. However, the horses are actually stronger than they seem and Tommy wants to put them in a couple inconspicuous races, have them win, and then quickly head out of town to the next racetrack before they get noticed. As they stable their horses at the track, an elderly stable hand nicknamed Medicine Ed for his ability to concoct powerful ointments for the animals, is instantly wary of the newcomers. Maggie latches onto him and looks to him as a mentor and advisor in the racing business. Maggie's presence is noted by the local horsing financier known as Two-Tie; he recognizes her as his long-lost, distant niece. Due to his regret over poor family decisions throughout his life, Two-Tie determines to protect and care for Maggie from a distance, always making sure she is happy and taken care of.

The races do not turn out as Tommy had planned; to make things worse for him, Maggie goes against his intuitions and makes a bit of money herself, which she uses to go in on a horse, Little Spinoza, with Medicine Ed and Deucey, another trainer at the stables. Little Spinoza is the grandson of a great racing legend named Speculation; however, he is a nervous and finicky horse who only succeeds when one jockey, named Alice, rides him. Tommy, in the meantime, struggles to pull together a back-up plan. Joe Dale, a horse-trainer and buyer who has become a corrupt womanizer using his power to bully others, sets his sights on Maggie, and schemes, in numerous ways, to get her under his power. He finally gets his chance when he is able to acquire a horse that Maggie is fond of, named Pelter. He dangles the horse in front of her, tempting her to come back to his stables, where he drugs her and tries to take advantage of her. However, Maggie is able to climb onto Pelter's back and flee the stables. Because she is drugged, however, she falls off of the horse. Fortunately, Two-Tie is there to rescue her—and the horse—from the situation by brandishing a gun. He threatens ban Joe Dale from the track. Joe backs down, but not before warning Two-Tie that the situation was not over yet. Joe later retaliates by kidnapping Two-Tie; in the...

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