To the naked eye there is no sharp boundary between true solutions, where solute molecules are fully dispersed in the solvent, and colloidal solutions, where the solute molecules form very small (diameter < 50 nm) water-soluble aggregates, and smaller aggregates (diameter < 5 nm) are not easily detected by light scattering. In some cases small aggregates can have higher affinity than the individual test molecules for some specific receptors, but most activity studies are based on interactions of individual test molecules with some specific receptor and, thus, it is more likely that aggregate formation will result in decreased apparent activity during high throughput screening (HTS) and false negative results. Furthermore, aggregate formation will influence the physicochemical properties of drugs, such as their aqueous solubility, chemical stability and partitioning. Formation of drug/cyclodextrin inclusion complexes can be used to mimic nonspecific drug-receptor interactions. Studies in aqueous cyclodextrin solutions have shown that practically insoluble drugs (solubility < 0.05 mg/ml) form small molecular aggregates and formation of such aggregates increases with decreasing drug solubility. Novel methods for solubility determinations, which can distinguish between individual solute molecules and small molecular aggregates, can possible improve the efficacy of HTS for new drug candidates.