There is no single perfect refrigerant for diverse air conditioning, refrigeration, and industrial applications. The predominant halocarbons (CFCs, HCFCs, and HFCs) combine excellent efficiency and safety with acceptable costs. However, they contribute to ozone depletion potential (ODP) and/or global warming potential (GWP). The Montreal Protocol has eliminated ODP by requiring replacement of CFCs and HCFCs with HFCs such as R-410A, R-407C, and R134a. The next focus is a worldwide technical and policy search for next-generation refrigerants with low global warming potential (LGWP). Potential options include “natural” refrigerants such as carbon dioxide (CO2), hydrocarbons (HC), and ammonia (NH3) as well as HFOs and HFO/HFC blends. All involve significant trade-offs among GWP, energy efficiency, safety, and cost. Environmental policy must consider the indirect effects of increased CO2 emissions for less efficient refrigerants, not just the direct global warming (GWP) of the refrigerant. We must insist on using metrics such as Total Equivalent Warming Impact (TEWI) that balance refrigerant direct GWP, charge level, leakage emissions, and efficiency of the refrigerant in actual systems. This allows the best possible comparison of refrigerants for each application. In the right policy environment, we can achieve reduced environmental impact and increase efficiency. This will probably require increased differentiation of application-specific refrigerant choices that are associated with somewhat higher first costs but very attractive life cycle costs with acceptable safety and environmental impacts.