Refrigeration systems are very important to chemical/petrochemical process industries because their performances are closely related to product quality, energy usage efficiency, and plant profitability. Hitherto, the optimal synthesis of a cascade refrigeration system with multiple refrigerants and multiple temperature levels presents considerable challenges and systematic studies combined with thermodynamic insights and mathematical-programming approaches in this area are still lacking. In this paper, a general methodology for the optimal synthesis of such cascade refrigeration system to maximize the energy efficiency has been developed. The exergy-temperature chart combined with the exergy analysis is presented to comprehensively analyze the thermodynamic nature of a refrigeration system, which provides a solid foundation for the conceptual design/retrofit of the complex refrigeration system. An exergy-embedded MINLP model has also been developed for the optimal synthesis of a general cascade refrigeration system. The efficacy of the developed methodology is demonstrated through a case study on the retrofit of a cascade refrigeration system for an ethylene plant. Published by Elsevier Ltd.