Enthalpy–entropy compensation (EEC) referred to the behavior of a series of closely related enzyme reactions exhibits a linear relationship between one of the following kinetic or thermodynamic parameters and isokinetic or thermodynamic temperatures. The enthalpy–entropy compensation effect in enzymatic catalysis was first described by Likhtenshtein in 1966. In this chapter, separate sections are devoted to statistical artifacts at apparent enthalpy–entropy compensation, theoretical consideration of EEC, EES for small molecules, EES for peptides and proteins, and miscellaneous examples of EEC in enzyme catalysis. The following compensation pairs of energy–entropy activation were considered: hydrolysis catalyzed by carboxypepsidase, transformation fumarate to malate catalyzed be fumarase, α-amylase reaction of starch hydrolysis, reactions catalyzed by unvertase, urease, lipase as well as enthalpy–entropy compensation at binding various inhibitors with catalase, and at inhibition bacterial luminescence. The predominant contribution of water reorganization to the thermodynamic and kinetic parameters of enzymatic reactions was stressed.