Abstract: The growing speed of biological evaluation of potential drug substances during the past years has imposed the need to develop new methods for the fast and efficient generation of new chemical entities. In general, chemical libraries containing large numbers of compounds may be prepared either on polymer supports or in solution. The use of supported reagents combines the advantages of polymer-supported reactions (e.g. allowing the application of a large excess of the reagent without the need for additional purification steps) with the benefits of solution phase chemistry (e.g. the ease of monitoring the progress of the reaction by simply applying LC-MS or TLC techniques). While, many solid-supported reagents have been described, only a few have been used in combinatorial chemistry. Furthermore, multi-step sequences using polymer-supported reagents are rare, although there is a growing interest in sequestering agents on solid supports. Recent work in our group has focussed on the development of orchestrated multi-step methods using polymer-supported reagents for the preparation of chemical compound libraries.