During the last decade, many industrial and medical applications have shown a requirement for low-temperature-cooling usage (from −40 to −80 °C), which cannot be efficiently obtained via the conventional refrigeration systems usually employed for medium-temperature applications (from 0 to −40 °C). A proper ultra-low-temperature (ULT) refrigeration system design is essential to achieve the desired output. The performance can be maximised via the suitable selection of the configuration and refrigerant for a specific temperature range. This work contributes a detailed overview of the different systems and refrigerants used in ultra-low-temperature applications. Different systems, such as single-stage vapour compression, multi-stage, cascade, auto-cascade, and air refrigeration cycles, are presented and discussed. An energy analysis is then carried out for these systems identifying the optimal system design and refrigerant selection to achieve the highest performance. This paper aims to provide the reader with a comprehensive background through an exhaustive review of refrigeration systems suitable for ultra-low-temperature applications. The effectiveness of these systems is proven numerically, mainly based on the temperature level and purpose of the application.