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Summary:From climate change to hydraulic fracturing, and from drinking water safety to wildfires, environmental challenges are changing. The United States has made substantial environmental protection progress based on media-specific and single pollutant risk-based frameworks. However, today’s environmental problems are increasingly complex and new scientific approaches and tools are needed to achieve sustainable solutions to protect the environment and public health. In this article, we present examples of today’s environmental challenges and offer an integrated systems approach to address them. We provide a strategic framework and recommendations for advancing the application of science for protecting the environment and public health. We posit that addressing 21st century challenges requires transdisciplinary and systems approaches, new data sources, and stakeholder partnerships. To address these challenges, we outline a process driven by problem formulation with the following steps: a) formulate the problem holistically, b) gather and synthesize diverse information, c) develop and assess options, and d) implement sustainable solutions. This process will require new skills and education in systems science, with an emphasis on science translation. A systems-based approach can transcend media- and receptor-specific bounds, integrate diverse information, and recognize the inextricable link between ecology and human health.