Due to increasing concerns about global warming, various environmental regulations will eventually phase out refrigerants used in air conditioning and refrigeration systems (e.g., R-410A, R-404A). Several refrigerants have been proposed as replacements, offering a variety of global warming potential (GWP), levels of energy efficiency and flammability. Some of these options are synthetic HFC/HFO mixtures such as R-454C and R-455A while other are commonly called naturals such as R-290 (Propane) and R-744 (Carbon Dioxide). This study discusses the merits of the leading options for air Conditioning and refrigeration systems. The fundamental requirements (environmental, performance, safety) are employed to fairly evaluate these options. Performance data and Life Cycle analysis results for these options are presented. Overall, this study provides information needed to judge the prospects of getting adequate replacement for R-410A and R-404A in a long-term sustainable basis.