In this chapter we show results from an innovative multi-model system used to produce climate simulations with a realistic representation of the Mediterranean Sea. The models (hereafter simply referred to as the “CIRCE models”) are a set of five coupled climate models composed by a high-resolution Mediterranean Sea coupled with a relatively high-resolution atmospheric component and a global ocean, which allow, for the first time, to explore and assess the role of the Mediterranean Sea and its complex, small-scale dynamics in the climate of the region. In particular, they make it possible to investigate the influence that local air-sea feedbacks might exert on the mechanisms responsible for climate variability and change in the European continent, Middle East and Northern Africa. In many regards, they represent a new and innovative approach to the problem of regionalization of climate projections in the Mediterranean region. The CIRCE models have been integrated from 1951 to 2050, with initial conditions obtained from a long spin-up run of the coupled systems. The simulations have been performed using observed radiative forcing (solar constant, greenhouse gases concentration and aerosol distribution) during the first half of the simulation period and the IPCC SRES A1B scenario during the second half (2001–2050). The projections indicate that remarkable changes in the Mediterranean region climate might occur already in the next few decades. A substantial warming (about 1.5°C in winter and almost 2°C in summer) and a significant decrease of precipitation (about 5%) might affect the region in the 2021–2050 period compared to the reference period (1961–1990), in an A1B emission scenario. However, locally the changes might be even larger. In the same period, the projected surface net heat loss decreases, leading to a weaker cooling of the Mediterranean Sea by the atmosphere, whereas the water budget appears to increase, leading the basin to loose more water through its surface than in the past. The climate change projections obtained from the CIRCE models are overall consistent with the findings obtained in previous scenario simulations, such as PRUDENCE, ENSEMBLES and CMIP3. This agreement suggests that the results obtained from the climate projections are robust to substantial changes in the configuration of the models used to make the simulations. Finally, the CIRCE models produce a 2021–2050 mean steric sea-level rise that ranges between +6.6 cm and +11.6 cm, with respect to the period of reference. Within the CIRCE project the results obtained from these models have been used to investigate the climate of the Mediterranean region and its possible response to radiative forcing. Furthermore, the data have been made available for climate change impact studies that are included in the Regional Assessment of Climate Change in the Mediterranean that has been prepared in the context of the CIRCE project.