Abstract The Seine River basin in France (76,238 km 2 , 17 million (M) people) has been continuously studied since 1989 by the PIREN-Seine, a multidisciplinary programme of about 100 scientists from 20 research units (hydrologists, environmental chemists, ecologists, biogeochemists, geographers, environmental historians). Initially PIREN-Seine was established to fill the knowledge gap on the river functioning, particularly downstream of the Paris conurbation (12 M people), where the pressure and impacts were at their highest in the 1980s (e.g. chronic summer hypoxia). One aim was to provide tools, such as models, to manage water resources and improve the state of the river. PIREN-Seine gradually developed into a general understanding and whole-basin modelling, from headwater streams to the estuary, of the complex interactions between the hydrosystem (surface water and aquifers), the ecosystem (phytoplankton, bacteria, fish communities), the agronomic system (crops and soils), the river users (drinking water, navigation), and the urban and industrial development (e.g. waste water treatment plants). Spatio-temporal scales of these interactions and the related state of the environment vary from the very fine (hour-meter) to the coarser scale (annual – several dozen km). It was possible to determine the trajectories (drivers-pressures – state-responses) for many issues, over the longue durée time windows (50–200 years), in relation to the specific economic and demographic evolution of the Seine basin, the environmental awareness, and the national and then European regulations. Time trajectories of the major environmental issues, from the original organic and microbial pollutants in the past to the present emerging contaminants, are addressed. Future trajectories are simulated by our interconnected modelling approaches, based on scenarios (e.g. of the agro-food system, climate change, demography, etc.) constructed by scientists and engineers of major basin institutions that have been supporting the programme in the long term. We found many cumulated and/or permanent hereditary effects on the physical, chemical, and ecological characteristics of the basin that may constrain its evolution. PIREN-Seine was launched and has been evaluated since its inception, by the National Centre for Scientific Research (CNRS), today within its national Zones Ateliers (ZA) instrument, part of the international Long-Term Socio-Economic and Ecosystem Research (LTSER) network.< Réduire