Widespread interest in the use of room temperature ionic liquids (RTILs) as solvents in anhydrous biocatalytic reactions has largely been met with underwhelming results. Enzymes are frequently inactivated in RTILs as a result of the influence of solvent on the enzyme’s microenvironment, be it through interacting with the enzyme or enzyme-bound water molecules. The purpose of this chapter is to present a rational approach to mediate RTIL–enzyme interactions, which is essential if we are to realize the advantages of RTILs over conventional solvents for biocatalysis in full. The underlying premise for this approach is the stabilization of enzyme structure via multipoint covalent immobilization within a polyurethane foam matrix. Additionally, the approach entails the use of salt hydrates to control the level of hydration of the immobilized enzyme, which is critical to the activation of enzymes in nonaqueous media. Although lipase is used as a model enzyme, this approach may be effective in activating and stabilizing virtually any enzyme in RTILs.