An FMG (flexible multi-generation system) consists of integrated and flexibly operated facilities that provide multiple links between the various layers of the energy system. FMGs may facilitate integration and balancing of fluctuating renewable energy sources in the energy system in a cost- and energy efficient way, thereby playing an important part in smart energy systems. The development of efficient FMGs requires systematic optimization approaches. This study presents a novel, generic methodology for designing FMGs that facilitates quick and reliable pre-feasibility analyses. The methodology is based on consideration of the following points: Selection, location and dimensioning of processes; systematic heat and mass integration; flexible operation optimization with respect to both short-term market fluctuations and long-term energy system development; global sensitivity and uncertainty analysis; biomass supply chains; variable part-load performance; and multi-objective optimization considering economic and environmental performance. Tested in a case study, the methodology is proved effective in screening the solution space for efficient FMG designs, in assessing the importance of parameter uncertainties and in estimating the likely performance variability for promising designs. The results of the case study emphasize the importance of considering systematic process integration when developing smart energy systems. (C) 2016 Elsevier Ltd. All rights reserved.