To reach optimal/better conceptual designs of energy systems, key design variables should be optimized/adapted with system layouts, which may contribute significantly to system improvement. Layout improvement can be proposed by combining system analysis with engineers’ judgments; however, optimal flowsheet synthesis is not trivial and can be best addressed by mathematical programming. In addition, multiple objectives are always involved for decision makers. Therefore, this paper reviews progressively the methodologies of system evaluation, optimization, and synthesis for the conceptual design of energy systems, and highlights the applications to thermal power plants, which are still supposed to play a significant role in the near future. For system evaluation, both conventional and advanced exergy-based analysis methods, including (advanced) exergoeconomics are deeply discussed and compared methodologically with recent developments. The advanced analysis is highlighted for further revealing the source, avoidability, and interactions among exergy destruction or cost of different components. For optimization and layout synthesis, after a general description of typical optimization problems and the solving methods, the superstructure-based and -free concepts are introduced and intensively compared by emphasizing the automatic generation and identification of structural alternatives. The theoretical basis of the most commonly-used multi-objective techniques and recent developments are given to offer high-quality Pareto front for decision makers, with an emphasis on evolutionary algorithms. Finally, the selected analysis and synthesis methods for layout improvement are compared and future perspectives are concluded with the emphasis on considering additional constraints for real-world designs and retrofits, possible methodology development for evaluation and synthesis, and the importance of good modeling practice.