The late 1980’s to mid-1990’s ushered exciting developments in pharmaceutical research worldwide. With innovative tools and techniques provided by combinatorial chemistry and molecular biology, a tremendous amount of effort and money was invested into the application of highly efficient high-throughput screening (HTS) technologies that could screen thousands of compounds at a time. However, medicinal chemists were confronted with the painful realization that the chemical space was too vast to be fully explored. The understanding emerged that library size was not paramount, and that the diversity of molecules in the library is a critical determinant for the success of any screening campaign. Early combinatorial libraries sacrificed diversity in order to accommodate facile reaction and purification methodologies, resulting in the production of collections of compounds that lacked structural complexity.