This review focuses on the application of molecular modeling and structure‐informed design (SID) to drug discovery. Routine utilization of quantum mechanical techniques allows generation of SID hypotheses, based on first principles. The authors introduce the concept of combining information from electrostatic potential surfaces and nonbonding orbitals to determine the nature and directionality of intermolecular interactions, particularly those that are infrequently exemplified in the protein data bank. © 2013 Wiley Periodicals, Inc. Ongoing improvements in computational throughput have made the application of quantum chemical methods more routine in drug discovery. Recent X‐ray crystal structures of inhibitors exhibiting nontraditional interactions with their protein targets, through halogens or sulfur containing heterocycles, provide an opportunity to apply these techniques. This review discusses several examples of these types of interactions and outlines strategies for incorporating descriptions of electrostatic potential surfaces and non‐bonding orbitals into the drug discovery process.