The protection of human and ecological health has become more challenging because of the myriad of human and climate stressors, and the sustainability of our social, economic, and environmental systems would be enhanced by further defensible risk assessment. There are scientific, technological, and cultural challenges to interoperability, bridging the necessary disciplines and integrating data from the genome to globe. Interoperability makes possible the use and reuse of data and modeling approaches and is a contemporary and rapidly progressing area advancing toxicology and exposure science. We present a coherent vision of human and ecological risk assessment, including the types of information and modeling science to create knowledge and apply it for improved decision-making. We focus on science-based decision-making, emphasizing decisions where science is the primary or sole driver, as in human toxicology and ecological risk assessment. This contrasts with decision-making where science has a minor role, if at all, in weighing decision options. We also examine the barriers that exist in the creation and application of systems thinking. We identify: the (1) needs and challenges for the application of a systems approach to informing decisions; (2) case studies that illustrate informatics needs for 21st-century science-based decision-making; and (3) recommendations on how to progress towards a systems approach to informing decisions.