In recent years, DNA-encoded libraries and reaction based virtual libraries have increasingly been deployed in drug discovery. These vast libraries push the limits of available, readily synthesizable chemical space. So far there are limited solutions to search within these structure sets. Substructure search and similarity analysis are far more challenging when libraries reach very large sizes. We discuss several technologies to efficiently analyze very large libraries. These tools can help researchers assess the chemical space covered by multiple chemical libraries and aid in hit expansion, scaffold hopping, and idea generation.