ORC technology is one of the most promising technologies for the use of residual energy in the generation of electrical energy, offering simple and environmentally friendly alternatives. In this field, the selection of working fluids plays an important role in the operation of the cycle, whether in terms of the energy efficiency or the minimization of environmental impacts. Therefore, in this paper, a comprehensive review is presented on the use of R1234yf refrigerant and its mixtures as working fluids in ORC systems. These fluids are used in low- and medium-temperature applications for the use of residual energy generated from solar energy, geothermal energy, and internal combustion engines. It was concluded that R1234yf and its mixtures are competitive as compared with conventional refrigerants used in ORC.