In the recent past, there has been a tremendous increase in the kind of data being generated by high-throughput analysis (omics) for endocrine disruptors (EDs). In parallel, several in silico tools [physiologically based pharmacokinetic (PBPK), pharmacodynamic (PD), systems biology and adverse outcome pathways (AOPs)] offer an opportunity to understand the biological complexity of EDs and environmental risk assessment. Along with the development of new tools and techniques in toxicological research, it is also necessary to have a continuous re-evaluation of existing data, data integration, and knowledge-based translation that might enable assessment of the human health risk of EDs. There is a need for a platform that integrates in vitro, in vivo, and several in silico models into one framework to directly tie the results to a predictive adverse outcomes model. The objective of this chapter is to introduce an in silico framework that integrates several models at the organ, molecular, cellular and genetic scale, we hereby describe integrative systems toxicology approaches that could be used in the human health risk assessment for EDs. This integrative systems toxicology will offer a quantitative understanding of the EDs adverse effects on a biological system, through the integration of exposome–internal exposure–molecular or cellular response to the adverse stimulus. Such in silico platform will be a dynamic tool to efficiently reduce the risk of EDs for public health.