Abstract A comprehensive multi-objective optimization framework is proposed to address the energy retrofit of typical villas on Mediterranean coastlines. Primary energy consumption and global cost are minimized using a Pareto approach. Two different construction technologies (i.e., a lightweight house in reinforced concrete and a massive tuff-made villa), in two different climates (i.e., Greek and Italian coasts), are investigated to provide robust optimal retrofit strategies according to two different criteria, i.e., the achievement of the nearly zero energy standard and the cost-optimality, respectively. The optimal energy retrofit strategies are achieved by coupling transient energy simulations and a genetic algorithm. They address all main factors affecting energy performance, i.e., building envelope (thermal insulation, reflectance of coatings, windows and solar shading), active energy systems (space conditioning devices) and renewable energy sources (solar photovoltaics). The investigation findings can provide useful generic guidelines for the retrofit of houses on the Mediterranean coastlines with a view to energy-efficiency and cost-effectiveness. The implementation of the suggested retrofit strategies to the case studies can yield substantial primary energy savings, up to 125 kWh/m2a, and global cost savings, up to 140 €/m2. The most energy-efficient and cost-effective retrofit solutions are the improvement of energy systems’ efficiency, the installation of full-roof photovoltaic systems, the replacement of windows and the roof thermal insulation.