The recent invasion of cane toads into the Northern Territory of Australia has resulted in a massive increase in mortality of some native squamate predators such as goannas. However, our field work demonstrate that a small number of goannas are able to persist in cane toad infested areas. Recent studies have suggested that propensity to feed on toxic prey, and/or morphological change could explain why some squamate predators are able to persist in such areas. We have recently identified a gene that provides resistance to toad toxins in some squamate reptiles, and therefore suggest that an additional explanation for the persistence of goannas in cane toad infested areas could involve selection on cane toad toxin resistance. As no members of the family Bufonidae are native to Australia, we propose that such selection should be traced to the evolutionary history of Australian goannas. These carnivorous lizards did not originate in Australia, and arrived to the Australian continent about 10 million years ago. The diet of all non-Australian goannas frequently include toads, demonstrating that all of these taxa are resistant to toad toxins, and strongly suggests that when arriving to the Australian continent, goannas were resistant to toad toxins. However, the absence of toad on the Australian continent most likely resulted in a relaxed selection in maintaining such a resistance. Our preliminary studies demonstrate that non-Australian goannas harbour the resistance gene, whereas Australian goannas do not. However, we have documented a substantial individual variation in this gene in the indigenous, Varanus panoptes, albeit none, so far, having an exact copy of the resistance gene. If a gene providing increased resistance to cane toad toxin is the main selective agent ensuring survival, we expect that the frequency of such a gene would increase dramatically among the surviving goannas.