The Mediterranean basin is a particularly vulnerable region to climate change, partly due to its quite unique character that results both from physiographic conditions and societal development. The region features indeed a near-closed sea surrounded by very urbanised littorals and mountains from which numerous rivers originate. This results in a lot of interactions and feedbacks between oceanic–atmospheric–hydrological processes that play a predominant role on climate and extreme events that frequently cause heavy damages and human losses in the Mediterranean. These highimpact weather events are heavy precipitation and flash flooding during the fall season, severe cyclogenesis associated with strong winds and large swell or heat waves and droughts accompanied by forest fires during summer. If during the last decade, numerical weather prediction (NWP) have made considerable progress in terms of realistic modelling of intense events, especially with the implementation by national weather services of convection-permitting models, they still have difficulties to predict the precipitation location and amount with the precision required to drive hydrological models, and more generally, to meet societal demands in the field of early warning and risk prevention. One of the current challenges is to quantify the uncertainties associated with these atmospheric model forecasts and to study their spread throughout the forecasting and warning chains. Also, the Mediterranean region is qualified as a “hot spot” for climate change. However, the evolution of intense events in the Mediterranean with climate change is still an open question. Studies on the evolution of extremes with climate change rely on a cascade of models and methods; all sources of uncertainty that need to be better quantified to assess the likelihood of climate projections and of their impacts. The MEDUP project (2008–2011), sponsored by the French National Research Agency (ANR) Vulnérabilité Milieux et Climat program, focused on these issues. Its objectives were to quantify and reduce the uncertainties associated with NWP and regional climate models and to study how they propagate on the environment and may combine with the intrinsic uncertainties of the vulnerability and risk analysis methods. An original feature of MEDUP was to address these questions at one and the same time for weather forecasting (1–4 day range), seasonal forecasting (1–3 month range) and climate scenario simulations (50–100 yr range). MEDUP was also innovative in considering the whole uncertainty chain, from the atmospheric modelling of high-impact weather events to their consequences on the environment. The region of interest was the northwestern Mediterranean in southern France, a region with complex coast shapes and mountains. Highimpact weather events considered in MEDUP are heavy precipitation, severe winds and long dry weather periods (favouring droughts). This special issue of Natural Hazards and Earth System Sciences contains 14 articles presenting most of the studies carried out within the MEDUP project. In the following, we summarize, for each of the prediction ranges, the content and main results of the papers published in this special issue together with references to some other studies performed within MEDUP.