Humans, in conjunction with natural top-down processes and through a sequence of cascading trophic interactions, may have contributed to the Pleistocene megafaunal extinctions. The arrival of the first humans, as hunters and scavengers, through top-down forcing, could have triggered a population collapse of large herbivores and their predators. We present evidence that the large mammalian herbivores of the North American Pleistocene were primarily predator limited and at low densities, and therefore highly susceptible to extinction when humans were added to the predator guild. Our empirical evidence comes from data on carnivore dental attrition, proboscidean age structure, life history, tusk growth rates, and stable isotopes from the fossil record. We suggest a research agenda for further testing of this hypothesis that will provide a more detailed comprehension of late Pleistocene megafaunal ecology, and thereby allow us to better understand and manage remaining megafauna.