Refrigerant significantly influences the performance of air-conditioning and refrigeration system as well as it has some environmental issues that need to be considered before selection. These systems can be made eco-friendly, if it is powered by solar energy or low-grade thermal energy and they use environment-friendly refrigerants. In this chapter, low GWP (global warming potential) refrigerants have been explored for the domestic air-conditioning applications. Refrigerants with high GWP are mostly used in environment control applications such as heating, ventilation, air-conditioning (HVAC), and refrigeration systems. Some refrigerants contribute to significant environmental issues and the Montreal Protocol and Kyoto Protocol have been signed to address the threats of ozone layer depletion and global warming potential. To fulfil the commitments of Kyoto Protocol, meanwhile, governments in many countries instituted phase-out plan for the use of environmentally harmful gasses in heat pump systems. For instance, EU MAC Directives, F-gas regulation, and Japan METI directives, which clearly declared their target year to use new refrigerant of GWP below 150 for mobile air conditioner and GWP below 750 for the residential air conditioner. Research interest has been stimulated to find alternative refrigerants with low or ultra-low GWP for energy conservation and environmental sustainability. Hydrofluoroolefins (HFOs) have a very low environmental impact, and thus HFOs are considering as potential candidates to replace the hydrofluorocarbon (HFC) refrigerants such as R410A, a near-azeotropic mixture of difluoromethane (R-32) and pentafluoroethane (R-125) and is commonly used refrigerant in air-conditioning applications. The limited number of pure fluids sometimes cannot meet the excellent heat transfer criteria due to their low volumetric capacity and moderate flammability or toxicity. Mixing of HFOs and HFCs refrigerants, in this case, allows the adjustment of the most desirable properties of the refrigerant by varying the molar fraction of the components. Different combination of mixture presented here cannot be claimed as the best mixture, but it might be a good choice for further study. This chapter focuses on the research trend in finding low GWP refrigerants and its application in different heat pump system considering the system performance, safety, and the overall environmental impact. The conventional vapor compression system, thermally driven adsorption system, and sorption-compression hybrid system have been taken into consideration.