New Zealand has many invasive vertebrate species that adversely affect native biota, compete with livestock, and spread diseases. Large-scale management of the most critical pests is achieved mainly by lethal control. This includes aerial application of the controversial toxin sodium fluoroacetate (1080), despite vociferous opposition from those concerned about potential non-target deaths, environmental contamination, and animal welfare impacts. We have borrowed a framework from animal welfare science, namely the ‘3Rs’ (reduction, refinement, and replacement), to address some of the concerns about the use of aerial poisoning while sustaining its cost-efficiency. The first aim was to reduce the amount of toxin used so that undesirable nontarget impacts are minimised. A range of projects have: 1) developed a method to identify the high-risk habitat within a landscape that needs to be targeted and, equally importantly, the low-risk habitat over which toxic bait does not need to be sown; and 2) optimised the combinations of prefeeding, sowing rate, and bait distribution to achieve the desired percentage kills at the lowest cost and lowest sowing rate of poison bait. To address the second aim, refining toxin use, we have improved target specificity by developing repellents to minimise unintended bykill of non-target species such as deer, and by identifying long-term strategies that minimise the total number of animals killed. The final aim, replacement of 1080, focuses on the search for alternatives, such as fertility control. It also involves development of complementary tools, such as tuberculosis vaccines, that may reduce the frequency or need for repeated use of 1080. This integrated ‘3Rs’ approach has quickly led to changes to operational practice by management agencies, with some operations now using up to 92% less toxic bait than usual, and other operations switching from aerial 1080 poisoning to ground-based non-1080 approaches for ongoing control. Looking forward, the ‘3Rs’ approach offers a framework for continuous improvement in the use of control tools for a wide range of species, whilst also providing a clear pathway to complementary or alternative approaches.