This publication presents the Agenda for the Americas on Health, Environment, and Climate Change 2021–2030 (the Agenda). The Agenda is a call to action to the health sector to lead the charge to address environmental determinants of health in the Americas. The Pan American Health Organization (PAHO) will work with Member States to achieve its goal and objective to ensure healthy lives and promote well-being for all at all ages using a sustainable and equitable approach that places a priority on reducing health inequity. The Agenda has been developed under the umbrella of the WHO Global Strategy on Health, Environment, and Climate Change, and builds upon the commitments set forth in the Sustainable Health Agenda for the Americas 2018–2030 and the PAHO Strategic Plan 2020–2025. The Agenda was developed in consultation with the Technical Advisory Group and through a consensus-driven decision-making process with Member States during the 2019–2020 period. Looking toward the achievement of Sustainable Development Goal 3, the Agenda focuses on: improving the performance of environmental public health programs and institutions; fostering environmentally resilient and sustainable health systems; and promoting environmentally healthy and resilient cities and communities. Its implementation will be context-specific, based on the needs and realities of the countries. It will benefit countries and territories by promoting good governance practices, strengthening the leadership and coordination roles of the health sector, fostering cross-sectoral action, focusing on primary prevention, and enhancing evidence and communication. It will facilitate access to human, technical, and financial resources necessary to address environmental determinants of health and ensure that the Region is fully engaged in global health, environment, and climate change processes and agreements. The objective of the Agenda is to strengthen the capacity of health actors in the health and non-health sectors to address and adapt to environmental determinants of health (EDHs), prioritizing populations living in conditions of vulnerability, in order to meet Outcome 18 of the PAHO Strategic Plan 2020–2025 directly and several other outcomes of the Plan indirectly. To address and adapt to the challenges of EDHs in the Region, an integrated and evidence-informed approach within the health sector and across sectors will be needed, one enabled, and supported by good governance practices, adequate management mechanisms, high-level political will, and adequate human, technical, technological, and financial resources.