The Mediterranean region is one of the most responsive areas to climate change and was identified as a major “hot-spot” based on global climate change analyses. This study provides insight into local climate changes in the Mediterranean region under the scope of the InTheMED project, which is part of the PRIMA programme. Precipitation and temperature were analyzed in an historical period and until the end of this century for five pilot sites, located between the two shores of the Mediterranean region. We used an ensemble of 17 Regional Climate Models, developed in the framework of the EURO-CORDEX initiative, under two Representative Concentration Pathways (RCP4.5 and RCP8.5). Over the historical period, the temperature presents upward trends, which are statistically significant for some sites, while precipitation does not show significant tendencies. These trends will be maintained in the future as predicted by the climate models projections: all models indicate a progressive and robust warming in all study areas and moderate change in total annual precipitation, but some seasonal variations are identified. Future changes in droughts events over the Mediterranean region were studied considering the maximum duration of the heat waves, their peak temperature, and the number of consecutive dry days. All pilot sites are expected to increase the maximum duration of heat waves and their peak temperature. Furthermore, the maximum number of consecutive dry days is expected to increase for most of the study areas.