As we enter the "fourth generation" of refrigerants, we consider the evolution of refrigerant molecules, the ever-changing constraints and regulations that have driven the need to consider new molecules, and the advancements in the tools and property models used to identify new molecules and design equipment using them. These separate aspects are intimately intertwined and have been in more-or-less continuous development since the earliest days of mechanical refrigeration, even if sometimes out-of-sight of the mainstream refrigeration industry. We highlight three separate, comprehensive searches for new refrigerants in the 1920s, the 1980s, and the 2010s-that sometimes identified new molecules, but more often, validated alternatives already under consideration. A recurrent theme is that there is little that is truly new. Most of the "new" refrigerants, from R-12 in the 1930s to R-1234yf in the early 2000s, were reported in the chemical literature decades before they were considered as refrigerants. The search for new refrigerants continued through the 1990s even as the hydrofluorocarbons (HFCs) were becoming the dominant refrigerants in commercial use. This included a return to several long-known natural refrigerants. Finally, we review the evolution of the NIST REFPROP database for the calculation of refrigerant properties.