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Earth’s most recent major extinction episode, the Quaternary Megafauna Extinction, claimed two-thirds of mammal genera and one-half of species that weighed >44 kg between ≈50,000 and 3,000 years ago. Estimates of megafauna biomass (including humans as a megafauna species) for before, during, and after the extinction episode suggest that growth of human biomass largely matched the loss of non-human megafauna biomass until ≈12,000 years ago. Then, total megafauna biomass crashed, because many non-human megafauna species suddenly disappeared, whereas human biomass continued to rise. After the crash, the global ecosystem gradually recovered into a new state where megafauna biomass was concentrated around one species, humans, instead of being distributed across many species. Precrash biomass levels were finally reached just before the Industrial Revolution began, then skyrocketed above the precrash baseline as humans augmented the energy available to the global ecosystem by mining fossil fuels. Implications include ( i )an increase in human biomass (with attendant hunting and other impacts) intersected with climate change to cause the Quaternary Megafauna Extinction and an ecological threshold event, after which humans became dominant in the global ecosystem; ( ii ) withcontinued growth of human biomass and today’s unprecedented global warming, only extraordinary and stepped-up conservation efforts will prevent a new round of extinctions in most body-size and taxonomic spectra; and ( iii ) a near-future biomass crash thatwill unfavorably impact humans and their domesticates and other species is unavoidable unless alternative energy sources are developed to replace dwindling supplies of fossil fuels.