INTRODUCTIONThe need for understanding essential recognition events in chemistry and biology has directed great efforts toward the development of novel and selective chemosensors. Despite the recent advances in the general knowledge about molecular recognition processes and de novo design by using theoretical calculations, a complete understanding of the mechanisms that regulate the interaction between sensors and analytes is not always accessible. This limits our ability to predict the structural requirements necessary for the design of ideal chemosensors for each analyte. Combinatorial approaches, which were initially developed as a versatile tool for drug discovery, are based on the relatively easy production of a large number of structurally related compounds [1]. Such approaches have been used to develop novel chemosensors or to improve the performance of the existing ones, especially when little or no information about the molecular recognition is available. Additionally, combinatorial methodologies have remarkably improved the scope and speed of the screening and data processing procedures, facilitating the overall progression of sensor development.This chapter, which consists of four sections, reviews recent examples of how combinatorial chemistry has been applied for the design of chemosensors. The first two focus on those combinatorial approaches that create libraries with the eventual aim of identifying one selective sensor for one particular analyte. Initially, target-oriented libraries explored the derivatization of recognition motifs to discover new sensors for a particular analyte, and have been constructed employing a wide range of chemical structures: small molecules, naturally occurring polymers Chemosensors: Principles, Strategies, and Applications, First Edition. Edited by Binghe Wang and Eric V. Anslyn.