Rapid methods for ranking the solubility of compounds in aqueous media using commercial, 96-well ultraviolet-visible (UV-vis) and nephelometric plate readers are described. The methods were evaluated using commercially available compounds from a variety of structural classes as well as a series of structurally related compounds derived from combinatorial synthesis. Samples were predissolved in dimethyl sulfoxide (DMSO) and then added to the study solvent to attain a final concentration of DMSO in the aqueous solution of 5%. Comparison of filtration of the samples through nylon and poly(tetrafluoroethylene) (PTFE) membranes is also described. The solubility of the compounds determined using the UV-vis plate reader in the absorption mode (with samples filtered with the PTFE filter) as well as in the light scattering mode was in good agreement with that determined by high-performance liquid chromatography, with an average correlation of 0.95. Solubility data obtained using a 96-well nephelometer was also comparable (r(2) = 0.97). The nonequilibrium methods described in this study can be used to rapidly rank compounds from combinatorial libraries for solubility and can also give a general assessment of solubility prior to running additional high throughput screens in a drug discovery environment.