Reduced use of volatile organic compounds as solvents in chemical processes is highly desirable from a sustainability point of view. This is because many conventional organic solvents have high vapor pressures, which can lead to hazards including low flash points, high flammability, toxicity, and atmospheric pollution. In order to make decisions regarding solvent use in a chemical process, it is important to evaluate the options available both from a chemical point of view and also with regards to the environment and safety. The typical physicochemical properties and parameters that need to be considered are briefly described. An overview of the environmental, health, and safety criteria used to assess all solvent systems (traditional and environmentally friendly) is provided. The concept of life‐cycle assessment when applied to solvents in either a quantitative or a qualitative way is introduced. Guidance provided by industrial users of solvents, especially the pharmaceutical industry, is highlighted. A range of sustainable solvent systems are described in this chapter. These include: water, supercritical carbon dioxide, carbon dioxide‐expanded liquids, solvents of switchable polarity and volatility, room temperature ionic liquids and deep eutectic solvents, bio‐derived solvents (e.g., 2‐methyltetrahydrofuran and glycerol), and solvent‐free systems. Their advantages, disadvantages, and properties are discussed, and examples of chemistries performed in them are given. Biphasic systems based on sustainable solvents and aimed at allowing their more efficient use and potential catalyst recycling are described. These include water/bio‐derived solvent, supercritical carbon dioxide/water, and supercritical carbon dioxide/ionic liquid systems.