DNA-Encoded chemical Libraries (DEL) enable efficient screening of billions of drug-like small molecules for binding affinity to protein targets. With DEL, products of combinatorial chemical synthesis can be screened as a single mixture, because each compound is covalently linked to a DNA segment with a known identifying sequence. Affinity selection experiments are conducted to isolate small molecules which bind to protein targets under specific conditions, and DNA sequencing is used to identify binders and quantify enrichment. We have developed a DEL synthesis and screening platform in the Center for Drug Discovery at Baylor College of Medicine which utilizes novel on-DNA chemistries to generate both general and target-specific libraries. These libraries have produced hit series with robust structure-activity relationships for multiple target families. We have also developed enhanced data analysis strategies which allow for quantitative comparisons of enrichment from multiple screens, providing information such as target selectivity, locations of binding sites, and relative binding affinities. These strategies led us to the swift discovery of potent and selective hit compounds for a variety of targets with little additional medicinal chemistry optimization.