Fresh water is not uniformly distributed and sometimes it is unavailable in sufficient quantities where or when it is needed. The demand for clean and desalted water is growing rapidly, due to the steady increase of population, especially in developing countries or in arid parts of the globe. As a result, there is today a great need for fresh water and for reliable methods, such as desalination processes, to produce it. However, both thermal and membrane processes are energy intensive, and there is a clear interaction between the amount of energy consumed and the amount of fresh water being produced. This chapter investigates such energy–water interaction for a low-temperature multiple-effect desalination (MED) process coupled with thermal vapor compression using model-based techniques. In the first part, an overview on MED is provided, with special attention on the strengths and weaknesses of existing mathematical models. Then, a modified version of the model by Darwish et.al, including a better evaluation of thermodynamic properties and a faster convergence procedure, is presented and validated. A sensitivity analysis of the performance parameters with respect to the main design parameters and operative conditions is performed and discussed. The chapter concludes by performing an evaluation of energy input to the process in the form of specific energy associated with the motive steam and power consumption of the seawater pumping system. The trade-off between energy consumption and plant dimensions is discussed, with the aim of identifying the optimal design parameters.