This chapter investigates the cultural legacy of the “Great Epizootic”: a North American horse influenza that paralyzed transportation networks throughout the continent in 1872. Americans responded to this outbreak by recasting it in humorous ways, writing poems about horses behaving like sickened people and marvelous accounts of human laborers working as surrogate animals. Within these literary documents, the veterinary term “epizootic” began to acquire a different meaning associated with inexplicable breakdowns in human behavior. Through figures including Zora Neale Hurston, Kurt Vonnegut, and Flannery O’Connor; in media forms ranging from musicals like Whoopee! (1930) to more recent rap songs like Sir Mix-a-Lot’s “My Hooptie” (1989); and even, perhaps, in the origin of the word “oops,” these literary revisionings of the Great Epizootic left a rich but underappreciated legacy within the United States. Recovering this legacy can augment efforts within human–animal studies for renewed interspecies intimacies brought about by a recognition of our shared vulnerability to disease.