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Chemical Epitope Targeting is a novel technology developed for designing peptide ligands with high affinity and specificity against specific regions of a protein that may be inaccessible to small molecules or antibodies. In this review, we summarize the key steps and significant applications of this technology. Operating on the same principles as antibody-antigen interactions, this technique involves chemically synthesizing the region of interest on the protein, called the epitope, as a polypeptide with a biotin detection tag and a strategically placed alkyne or azide presenting amino acid. The constructed epitope is screened against a comprehensive linear or cyclic One Bead One Compound library of the corresponding azide or alkyne presenting peptides with approximately 2 million unique members. Binders in the correct orientation undergo proximity catalyzed azide-alkyne cycloaddition reaction and are detected using this copper free in situ click chemistry. Subsequent binding assays against the full protein identify high affinity peptide binders with dissociation constants in the nanomolar range. These monoligand peptides can be further developed into biligands and triligands, larger macromolecules with two or three peptide ligands connected by linkers, which have improved binding affinity for continuous or discontinuous epitopes. Application of this technology has yielded protease-resistant and cell-permeable compounds for potential therapeutic and diagnostic purposes. In this review, we highlight the different Chemical Epitope Targeted ligands developed for a range of applications, from differential detection of biomarkers and receptor isoforms to the inhibition of enzyme functions and stabilization of protein folding states.