Invasive and introduced species can pose major ecological challenges to vulnerable native wildlife. Toxic invaders can cause long-term disruptions of predator communities with consequent trophic cascade effects. Madagascar, a key global biodiversity hotspot, is experiencing an invasion by a toxic species, the toad Duttaphrynus melanostictus. Bufonid toads secrete bufadienolides that are fatal to many predator species by inhibiting the sodium-potassium-pump (Na+/K+-ATPase). However, multiple predator lineages have evolved resistance to these toxins through repeated, predictable and specific point mutations in the Na+/K+-ATPase gene. Here we analyse sequences of the Na+/K+-ATPase gene of a wide range of Malagasy species, including amphibians, birds, mammals and reptiles, and find that only one native species shows evidence of resistance to the novel toxin. The results strongly suggest that invasive toads are liable to have significant impacts on the native Malagasy fauna, and stress the importance of controlling the spread of this alien species to prevent a worsening biodiversity crisis.