Vertebrate pesticides for wild animal control in New Zealand came under scrutiny in the 1980s and 1990s, which engendered considerable research to update the toxicology databases of older compounds, such as 1080 or diphacinone, to meet current international registration standards. In parallel there was a focus on identifying “use patterns” and formulations that are effective at killing pests and less hazardous to other wildlife. Improved bait quality and reduced sowing rates for 1080 bait for possum control in New Zealand, down from 10-15 kg of bait per hectare to 1-3 kg, has been accompanied by increased effectiveness and reduced non-target risk. This has been coupled with an improved understanding of 1080 toxicology and risk communication amongst pest control professionals and with the community. In addition, in vivo metabolism and persistence studies coupled with field surveys have improved understanding of the toxicokinetics and non-target effects of different anticoagulants. This enabled improved choice of tools for island versus mainland use in New Zealand. The risks associated with “one-off” applications of baits containing second-generation anticoagulants for rodent eradication on islands are considered to be very substantially outweighed by the potential benefits to their ecosystems. On the mainland, contamination of wildlife and game species and risk of secondary poisoning have been substantially reduced by switching from second- to first-generation anticoagulants. Finally, these developments were coupled with the identification of improved baits for ground control of possums and rodents, such as encapsulated cyanide and gel baits containing cholecalciferol, which in turn reduced an over-reliance on 1080 and anticoagulants alone. Nevertheless, safer use patterns, improved formulations and target specificity, and new vertebrate pesticides are still required, and this will be a major challenge for the 21st Century.