Conventional approaches to toxicity testing and risk assessment are often decades old, costly and low-throughput, and of dubious relevance to humans. These factors have prompted leading scientific bodies to call for a transition to a 21st century paradigm, including a move away from apical outcomes at high doses in whole animals, and toward a mechanistic understanding of the source-to-outcome continuum between xenobiotic exposure and adverse health effects. Such a shift will require a robust understanding of the cellular response/toxicity pathways which that can lead to adverse effects when perturbed; appropriate in vitro systems to study chemical interactions at key targets along a pathway; and computational systems biology models to describe the “circuitry” underlying each pathway as a basis for creating biologically realistic dose-response models. The AXLR8 project aims to support the transition to a toxicity pathway-based paradigm for quantitative risk assessment, and to this end will: 1) Organise a series of scientific workshops and expert meetings to map and catalogue research progress, gaps and needs in the above areas. 2) Provide a range of tools and opportunities for enhanced interdisciplinary and international communication, coordination and collaboration in order to maximise the impact of available resources. 3) Work to streamline regulatory acceptance procedures to provide for the expeditious uptake of validated 3Rs methods, including a smooth transition to 21st century systems as they become available. 4) Produce an authoritative report on the state of the science, including a practical roadmap detailing priority research and funding targets, in order to ensure a prominent role for European science in this rapidly developing global research area.