Thermophilic organisms are found in hot places such as hot springs and hot vents at the bottom of the sea. Depending on the optimal growth temperature (Topt) thermophilic organisms are divided into two classes: moderate thermophiles (50°C < Topt < 80°C) and hyperthermophiles (Topt > 80°C). Given the fact that thermophilic proteins are made of the same building blocks as mesophilic proteins, it is important to understand the molecular basis of the mechanisms through which thermophilic proteins achieve their enhanced stability and maintain their activities at temperatures of 100°C or more. Extensive research has been conducted on the physicochemical origin of thermostability, and these studies have suggested that a variety of factors can contribute to this observed enhanced stability.2-12 Such factors include optimized electrostatic interactions, improved packing, networks of hydrogen bonds, hydrophobic interactions, and cavity ’lling.4,6,7,13-20 The enhancement of thermostability in thermophilic proteins is now believed to be the consequence of a number of locally improved interactions in three dimensions. For more detailed accounts of the physical basis of thermostability, see Chapters 1 through 4 in this book.