Although they were used historically as antimicrobial agents, there is a modern requirement to devise organic solvent systems for exploitation in the biotransformation by intact cells of substrates that are poorly soluble in water. Water-immiscible solvents are normally less cytotoxic than are water-miscible ones. While a unitary mechanism is excluded, damage to the membrane remains the likeliest major mechanism of cytotoxicity, and may be conveniently assessed using an electronic biomass probe. Studies designed to account for the mechanisms of action of general anesthetics and of uncouplers parallel those designed to account for the cytotoxicity of organic solvents. Although there are hundreds of potential physical descriptors of solvent properties, many are broadly similar to each other, such that the intrinsic dimensionality of solvent space is relatively small (< 10). This opens up the possibility of providing a rational biophysical basis for the optimization of the solvents used for biotransformations. The widely used descriptor of solvent behavior, log P (the octanol:water partition coefficient), is a composite of more fundamental molecular descriptors; this explains why there are rarely good correlations between cytotoxicity and log P when a wide variety of solvents is studied. Although the intrinsic dimensionality of solvent space is relatively small, pure solvents still populate it rather sparsely. Thus, mixtures of solvents can and do provide the opportunity of obtaining a solvent optimal for a biotransformation of interest.