In this paper, a methodology for multi-objective optimization of trigeneration plants is presented. It is primarily applicable to the systems for buildings' energy supply characterized by high load variations on daily, weekly and annual bases, as well as the components applicable for flexible operation. The idea is that this approach should enable high accuracy and flexibility in mathematical modeling, while remaining efficient enough. The optimization problem is structurally decomposed into two new problems. The main problem of synthesis and design optimization is combinatorial and solved with different metaheuristic methods. For each examined combination of the synthesis and design variables, when calculating the values of the objective functions, the inner, mixed integer linear programming operation optimization problem is solved with the branch-and-cut method. The applicability of the exploited metaheuristic methods is demonstrated. This approach is compared with the alternative, superstructure-based approach. The potential for combining them is also examined. The methodology is applied for multi-objective optimization of a trigeneration plant that could be used for the energy supply of a real residential settlement in Niš, Serbia. Here, two objectives are considered: annual total costs and primary energy consumption. Results are obtained in the form of a Pareto chart using the epsilon-constraint method.Energies 2014, 7 8555