High-throughput chemistry (HTC) is approaching its 20-year anniversary. Since 1992, some 5,000 chemical libraries, prepared for the purpose of biological investigation and drug discovery, have been published in the scientific literature. This review highlights the key events in the history of HTC with emphasis on library design. A historical perspective on the design of screening, targeted, and optimization libraries and their application is presented. Design strategies pioneered in the 1990s remain viable in the twenty-first century.