This publication presents a framework to implement the Agenda for the Americas on Health, Environment, and Climate Change 2021–2030 (the Agenda) that is structured around essential public health functions focused on environmental determinants of health. 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 was 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.