Low global warming potential (GWP) refrigerants for the next-generation air conditioning systems have been investigated with target domestic applications. High-GWP refrigerants are mostly used in climate control applications such as heating, ventilation and air conditioning (HVAC) and refrigeration systems. The majority of refrigerants are responsible for significant environmental issues such as ozone layer depletion and global warming. The Montreal Protocol and the Kyoto Protocol have been implemented to address such issues. In the meantime, authorities in many countries have taken the initiative to phase out the usage of environmentally harmful refrigerants in vapor compression refrigeration systems. Following the global warming mitigation scheme by many signatory countries, research interest has been focused on finding alternative refrigerants with low or ultra-low GWP. This study considered the research trend and development of low-GWP refrigerants while examining system performance, safety issues, and the equivalent environmental impact as the critical assessment parameters. Here, the focus is primarily set on the potential of refrigerant blends (HFCs + HFOs) where the GWP value of 300 is set as the threshold value. Targeted for domestic heat pump systems, the performance of such systems using various refrigerant blends is collated and discussed. Many blends offer innovative drop-in replacements for R410A-conforming F-gas regulations. The technical difficulties and realistic remedies for the existing refrigerants are also discussed.