The adoption of the EU F-Gas Regulation 517/2014 and the resulting development of the multi-ejector concept have led carbon dioxide to take center stage as the sole refrigerant (R744) in several applications. Therefore, a knock-on effect on the number of supermarkets relying on “CO2 only” refrigeration systems has been experienced. Additionally, a global consensus of commercial multi-ejector based R744 units is also intensifying as a consequence of both the promising results obtained and the other measures in force for environment preservation. Furthermore, the multi-ejector concept is expected to offer significant energy savings in other high energy-demanding buildings (e.g., hotels, gyms, spas) as well, even in warm climates. In this investigation, the evolution of R744 ejector supported parallel vapor compression system layouts for food retail applications was summed up. Furthermore, their technological aspects, the results related to the main theoretical assessments and some relevant field/laboratory measurements were summarized. Also, the experience gained in the adoption of the multi-ejector concept in transcritical R744 vapor-compression units aimed at other energy intensive applications was presented. Finally, the persistent barriers needing to be overcome as well as the required future work were brought to light.