This contribution addresses the multi-period synthesis of an optimally integrated regional biomass and bioenergy supply network through a mixed-integer linear programing (MILP) approach. The production processes from different sources of biomass include first, second, and third generations of biofuels like bioethanol, biodiesel, hydrogen, Fischer Tropsch diesel, and green gasoline. The aim is to maximize the sustainably viable utilization of resources by accounting for the competition between fuels and food production. An MILP model for efficient bioenergy network optimization based on four layers is extended to include several features, such as seasonality and availability of resources, enabling recycles of products and total site heat integration in order to address real-world applications with a systematic decisionmaking approach. The multi-period optimization of a heat-integrated biorefinery's supply network is performed through maximization of the economic performance. Economically efficient solutions are obtained with optimal selection of raw materials, technologies, intermediate and final product flows, and reduced greenhouse-gas emissions. (C) 2014 Elsevier Ltd. All rights reserved.