Enzyme activity in nonaqueous media (e.g. conventional organic solvents) is typically lower than in water by several orders of magnitude. There is a rising interest of developing new nonaqueous solvent systems that are more “water-like” and more biocompatible. Therefore, we need to learn from the current state of nonaqueous biocatalysis to overcome its bottleneck and provide guidance for new solvent design. This review firstly focuses on the discussion of how organic solvent properties (such as polarity and hydrophobicity) influence the enzyme activity and stability, and how these properties impact the enzyme’s conformation and dynamics. While hydrophobic organic solvents usually lead to the maintenance of enzyme activity, solvents carrying functional groups like hydroxys and ethers (including crown ethers and cyclodextrins) can lead to enzyme activation. Ionic liquids (ILs) are designable solvents that can conveniently incorporate these functional groups. Therefore, we systematically survey these ether- and/or hydroxy-functionalized ILs, and find most of them are highly compatible with enzymes leading to high activity and stability. In particular, ILs carrying both ether and tert-alcohol groups are among the most enzyme-activating solvents. Future direction is to learn from enzyme behaviors in both water and nonaqueous media to design biocompatible “water-like” solvents.