Apart from two species of bat, New Zealand has no extant endemic terrestrial mammals. Some live relatively commensally, while others are more parasitic on Aotearoa’s native and unique birdlife, taking full advantage of their predator naivety and flightlessness. In response to the devastating impact on some species there are several well established national programmes to control invasive mammal predators, in particular possums, stoats and rats. This has led to the formation of the Zero Invasive Predators (ZIP) and Predator Free New Zealand (PFNZ) groups, dedicated to the formidable challenge of removing these mammal pests by 2050. A major hurdle to this initiative is the exponential cost, in terms of both finance and time, of removing the last few surviving individuals from an invaded area using current techniques. Hence there is an urgent drive for the development of new tools using novel technologies to assist in the complete elimination of mammal predators from regions. Here, I present our “Achilles heel” approach. In effect, we rely on comparative genomics to select genes central to critical physiological control processes for specific knock-out in target species only, using highly sensitive gene-silencing RNA interference (RNAi) techniques, in particular siRNA. Two cases are discussed, feral pigs and brushtail possums, each with their own set of unique challenges.