This chapter discusses the methodology for the synthesis of truly sustainable system-wide supply networks is introduced by using a mathematical programming approach, with the objective of maximizing Sustainability Net Present Value. Since separate criteria are now merged, a multi-objective optimization problem is reduced to a single-objective one, which is particularly convenient for the synthesis of larger scale systems-and regional renewable supply networks are among such larger scale systems. The chapter presents an application of the above methodology to the synthesis of a supply network producing food, fuel and electricity for targeting the partial transition from fossil-based to renewable resources on a subcontinental scale of Central Europe over a time horizon of 20 years. A general MI(N)LP problem has been proposed, which comprises Sustainability Net Present Value as an objective, a multi-period MI(N)LP model for a System-Wide Supply Network, and additional sustainability constraints to direct the optimization procedure towards truly sustainable solutions.