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The polystyrene-based 2-chlorotrityl resin was originally used in the synthesis of peptides using an Fmoc-amino acid(slash)carboxyl-linked protocol. While traditionally employed to prepare a number of biologically active peptides, the resin has received increasing attention as a support for the synthesis of pseudopeptide and non-peptide molecules recently. This review focuses on 2-chlorotrityl resin-supported synthesis of small molecules that collectively display a broad range of biological activities.