DNA-encoded library (DEL) selections and high-throughput screens (HTS) offer different means to identify new molecules for drug discovery, each having their own advantages and limitations. Both methods have been used in countless successful campaigns and often either approach could be a viable way to pursue hit identification depending on the project and if the assay and/or target poses any method specific challenges. Some of these challenges can be anticipated, such as DNA binding proteins causing non-ligand dependent enrichment in DEL selections or pan-assay interference compounds in HTS. However, other problems are more difficult to predict and are only identified retrospectively. We have encountered projects where either the DEL campaign or the HTS campaign was successful, but the other was not. These outcomes highlight the fact that DEL and HTS have their own unique challenges. As a result, the best approach to ensure a successful hit identification program is to evaluate concurrent DEL and HTS campaigns. To better understand unforeseen challenges in DEL and HTS, here we discuss two case studies: one where DEL was successful and HTS was not, and another where HTS was successful and DEL was not.