DNA-encoded chemical libraries (DECLs) are an innovative technology that combines molecular biology and combinatorial chemistry to create and screen vast libraries of small molecules and peptides. DECLs, including DNA-encoded peptide libraries (DEPLs), leverage DNA as a molecular barcode, enabling the identification of binders through affinity selection and sequencing. Advanced techniques, such as DNA-encoded self-assembled chemical libraries (DESACLs), enhance library diversity by using DNA hybridization and self-assembly to produce dual pharmacophores, significantly advancing fragment-based drug discovery. The modular nature of DESACLs allows for dynamic assembly and combinatorial expansion, generating libraries with millions of combinations. This approach supports drug discovery by targeting complex biological interactions, such as protein–protein interfaces and provides a platform for molecular diagnostics.