Agricultural frontiers are dynamic environments characterized by the conversion of native habitats to agriculture. Because they are currently concentrated in diverse tropical habitats, agricultural frontiers are areas where the largest number of species is exposed to hazardous land management practices, including pesticide use. Focusing on the Amazonian frontier, we show that producers have varying access to resources, knowledge, control and reward mechanisms to improve land management practices. With poor education and no technical support, pesticide use by smallholders sharply deviated from agronomical recommendations, tending to overutilization of hazardous compounds. By contrast, with higher levels of technical expertise and resources, and aiming at more restrictive markets, large-scale producers adhered more closely to technical recommendations and even voluntarily replaced more hazardous compounds. However, the ecological footprint increased significantly over time because of increased dosage or because formulations that are less toxic to humans may be more toxic to other biodiversity. Frontier regions appear to be unique in terms of the conflicts between production and conservation, and the necessary pesticide risk management and risk reduction can only be achieved through responsibility-sharing by diverse stakeholders, including governmental and intergovernmental organizations, NGOs, financial institutions, pesticide and agricultural industries, producers, academia and consumers.