Tagging combinatorial libraries with DNA barcodes allows using a simple affinity selection protocol to rapidly identify protein binders. A primary challenge with such DNA-encoded libraries (DELs) is how to design them to provide the effective screening productivity needed for the routine discovery of developable hits. The predominantly pursued approach is to make platforms of very large libraries of chemically complex compounds. While many success stories have proven the validity of this paradigm, it is unclear whether such DELs compare favorably to competing technologies with regard to return-on-investment. Moreover, the often heterogeneous synthesis yields of very large libraries and undersampling of DNA-barcodes impedes effective hit triaging. The cost of producing large DEL platforms and identifying hits from screening data is completely prohibitive for laboratories with limited resources. We therefore explore alternative library designs with the goal of finding active compounds at lower DEL synthesis and lead-development costs. We custom-design DELs for specific target classes, and early studies have demonstrated that such libraries provide hits rapidly and economically. For example, a small and chemically simple DEL targeting NAD+-binding sites provided potent and target-selective hits for ADP-ribosyltransferases. Possible strategies for advancing early screening hits from such chemically simple libraries will be discussed.