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Human health and wellbeing and the health of the biosphere are inextricably linked. The state of Earth's life-support systems, including freshwater, oceans, land, biodiversity, atmosphere, and climate, affect human health. At the same time, human activities are adversely affecting natural systems. This review paper is the outcome of an interdisciplinary workshop under the auspices of the Future Earth Health Knowledge Action Network (Health KAN). It outlines a research agenda to address cross-cutting knowledge gaps to further understanding and management of the health risks of these global environmental changes through an expert consultation and review process. The research agenda has four main themes: (1) risk identification and management (including related to water, hygiene, sanitation, and waste management); food production and consumption; oceans; and extreme weather events and climate change. (2) Strengthening climate-resilient health systems; (3) Monitoring, surveillance, and evaluation; and (4) risk communication. Research approaches need to be transdisciplinary, multi-scalar, inclusive, equitable, and broadly communicated. Promoting resilient and sustainable development are critical for achieving human and planetary health.