The finding of carbon, silicon, and germanium based bicyclo[2.2.2]octanes as a class of effective quantum interference based single-molecule insulators emphasizes the need for further exploration of the structure-function relationship in s-conjugated molecules. With the perspective of inspiring new directions for research of insulating and dielectric materials, the search for single-molecule insulators continues to be an important prospect for molecular electronics. Supporting Information. Computational details; Supplementary results.