In this virtual thematic issue (VTI) the authors of 14 papers address key challenges of environmental modelling and software to support the identification of human and ecological health risks. The contributions address different pathways how environmental exposure can affect human health with a focus on models, data and software and can be divided into the following research areas: (1) modelling approaches to quantify air pollution concentrations and exposure, (2) models and methods to determine health effects of air pollution, (3) models and software to predict and quantify disease and health risks and (4) data interoperability and integration. These contributions highlight that further advances in this research field are required, especially from highly polluted regions, as so far papers from these regions are scarce. The majority of contributions covers exposure to ambient air pollution, which is a key public health risk in both industrialised and developing countries. While not a focus of this VTI, human exposure to water and soil contamination as well as exposure pathways through other environmental media are equally relevant. Further research into how modelling, software and data can support an integrated assessment of the whole Exposome is therefore essential.