The ‘EpiGeneSys’ Network of Excellence aims to enable European epigenetics research to enter the arena of systems biology, a new step forward with major implications for human health. Many diseases, not explained solely by gene mutation, have rather been associated with epigenetic disorders. Following the identification of key epigenetic regulators, a move towards a systems biology approach is needed to understand their dynamic functional relationships. This NoE identified 4 areas aiming at: 1) characterizing the molecular dynamics of epigenetic systems at the single molecule and cell level, 2) linking genotypes to epigenotypes, 3) investigating how environmental, developmental and metabolic signals act upon the epigenome, and 4) understanding epigenetic inheritance through replication, mitosis and meiosis. The common objective is to address fundamental epigenetic mechanisms in quantitative terms both spatially and temporally. The ultimate goal is to express the underlying dynamic events in mathematical terms in order to model and predict how the balance between maintenance and erasure of epigenetic information varies in specific developmental contexts under normal or pathological conditions. A major effort on data management and technology will provide standardised protocols for processing, normalising, and analysing each type of epigenetics data set. Common platforms, tools and resources including a key multilayer toolbox will be implemented for wide use and easy access for researchers, within the NoE and the epigenetics community at large. This NoE will function as an essential bridge between epigenetics researchers and the systems biology community. In the NoE, 22 teams will join efforts to address Epigenetics questions from a systems biology perspective. The combination of a strong training plan together with extension through open targeted calls to recruit young talent will further contribute to build a coherent new EpiGeneSys Area of European Research.