: DNA-encoded chemical libraries (DELs) have come of age and emerged to become a powerful technology platform for ligand discovery in biomedical research and drug discovery. Today, DELs have been widely adopted in the pharmaceutical industry and employed in drug discovery programs worldwide. DELs are capable of interrogating drug targets with an extremely large number of compounds highly efficiently. : In this review, the authors introduce the history of DELs and provide an overview of the major technological components, including encoding methods, library synthesis, chemistry, selection methods, hit deconvolution strategy, and post-selection data analysis. A brief update on the hit compounds recently discovered from DEL selections against drug targets is also provided. Finally, the authors discuss their views on the present challenges and future directions for the development and application of DELs in drug discovery. : DELs have provided great opportunities for lead compound discovery at an unprecedented scale and efficiency in drug discovery. The key to the future success of DELs as true discovery modalities, rather than just 'a way to make many compounds,' is to go beyond physical binding to functional or even phenotypic assays with the capability to probe the biological system.