This Special Issue addresses the general problem of a proper match between the demands of energy users and the units for energy conversion and storage, by means of proper design and operation of the overall energy system configuration. The focus is either on systems including single plants or groups of plants, connected or not to one or more energy distribution networks. In both cases, the optimum design and operation involve decisions about thermodynamic processes, about the type, number, design parameters of components/plants, and storage capacities, and about mutual interconnections and the interconnections with the distribution grids. The problem is very wide, can be tackled with different methodologies and may have several, more or less valuable and complicated solutions. The twelve accepted papers certainly represent a good contribution to perceive its difficulty.Keywords: smart power systems; multi-energy systems; optimization of energy systems design and operation