Our understanding of mammalian predation on salamanders is primarily restricted to small carnivorous species (i.e., shrews). We conducted a series of investigations to determine whether the Virginia opossum (Didelphis virginiana) is a predator of various salamander species [Desmognathus fuscus, Plethodon dorsalis, and Notophthalmus viridescens (adult and eft)] from the eastern United States. All species, including toxic newt efts, were palatable to opossums. These results suggest opossums could be an active predator of salamanders. In a second study, each terrestrial salamander species exhibited avoidance responses to kairomones from opossums indicating that despite a significant risk of mortality each salamander has evolved mechanisms to minimize predation risk. Combined with overlapping habitat preferences, foraging behavior that places them in contact, and a dietary preference for animal matter, these data suggest opossums may be an important predator on terrestrial salamanders.