From the late Pleistocene to the Holocene and now the so-called Anthropocene, humans have been driving an ongoing series of species declines and extinctions (Dirzo et al. 2014). Large-bodied mammals are typically at a higher risk of extinction than smaller ones (Cardillo et al. 2005). However, in some circumstances, terrestrial megafauna populations have been able to recover some of their lost numbers because of strong conservation and political commitment, as well as human cultural changes (Chapron et al. 2014). Indeed, many would be in considerably worse predicaments in the absence of conservation action (Hoffmann et al. 2015). Nevertheless, most mammalian megafauna face dramatic range contractions and population declines. In fact, 59% of the world's largest carnivores (more than or equal to 15 kilograms, n = 27) and 60% of the world's largest herbivores (more than or equal to 100 kilograms, n = 74) are classified as threatened with extinction on the International Union for the Conservation of Nature (IUCN) Red List (supplemental tables S1 and S2). This situation is particularly dire in sub-Saharan Africa and Southeast Asia, home to the greatest diversity of extant megafauna (figure 1). Species at risk of extinction include some of the world's most iconic animals—such as gorillas, rhinos, and big cats (figure 2 top row)—and, unfortunately, they are vanishing just as science is discovering their essential ecological roles (Estes et al. 2011). Here, our objectives are to raise awareness of how these megafauna are imperiled (species in tables S1 and S2) and to stimulate broad interest in developing specific recommendations and concerted action to conserve them.