Sustainability and energy efficiency issues, connected to the search for fuel consumption reductions and to the more and more mandatory international regulations regarding the emissions of atmospheric pollutants, are acquiring a growing relevance in shipping industry. In this context, the integration of forecasting resources for meteo-marine conditions with the capability of performing detailed ship performances simulations may give relevant contributions to improve the in service energy efficiency of ships through the use of weather routing systems. These systems are today widely used, almost in transoceanic navigation, and their effectiveness may be improved if they are utilized in integration with other energy efficiency measures and with observing systems for ship responses and encountered meteo-marine conditions. The work here reported has been developed in the context of the PROFUMO project, financed by the European Space Agency, in the framework of the IAP Artes 20 Programme for Feasibility Studies. Part of the project activities are devoted to perform numerical simulations of ship seakeeping and powering performances along Mediterranean routes, by the use of high resolution wind wave forecasts data produced by the operational service of Consorzio LaMMA. With this aim, in particular a numerical model of a real Ro-Ro ship has been constructed and the results of the numerical simulations are exploited to evaluate the potential impact of the variability of meteo-marine forecasting skills on weather routing and to estimate the potential contribution to fuel savings of meteorological route optimization at the Mediterranean scale.