The optimal synthesis of the refrigeration configuration and the selection of the best refrigerants that satisfy a set of process cooling duties at different temperatures is addressed. This approach simultaneously selects refrigerants and synthesizes refrigeration structures by minimizing a weighted sum of investment and operating costs. A superstructure representation considers the majority of refrigeration cycle features encountered in real complex multistage refrigeration cycles such as economizers, multiple refrigerants, and heat integration. A novel theoretical treatment of modeling representations and algorithmic improvements is introduced. Results, for example, involving multiple refrigerants, cooling loads, and heat sinks are obtained. Complex, nonintuitive topologies typically emerge as the optimal refrigeration configurations that are better than those obtained when refrigeration synthesis is performed after refrigerant selection.