Chemotypes are presented as a way of selecting a handful of nonoverlapping substructures for a molecular structure representing such things as ring systems and formal counterparts of functional groups. By taking positioning into account, chemotypes can be viewed as a priori postulates of the critical substructure of a compound should it become a lead. The construction and use of efficient single-coverage sublibraries involving cyclic systems, ring systems, and functional groups are presented and illustrated in a case study involving 12 competitive inhibitors of DHFR that emerged in screening the McMaster 50K training library. A 10K single-coverage sublibrary involving positioned functional groups uncovered 10 of the competitive inhibitors and all of the regions with interesting activities giving rise to an a priori enhancement ratio of 4.2. The reasoning underlying the construction of these sublibraries, the corresponding chemotypic logic of followup screening, and the consequential generation of multiscaffold SAR data are presented using the data in this case study.