Covering: up to March, 2013. This article was invited following the 2012 NPR Lectureship presented to Professor Dean Tantillo at the 21st IUPAC International Conference on Physical Organic Chemistry (ICPOC 21) This Highlight describes applications of quantum chemical calculations to problems in natural products chemistry, including the elucidation of natural product structures (distinguishing between constitutional isomers, distinguishing between diastereomers, and assigning absolute configuration) and determination of reasonable mechanisms for their formation. Applications of quantum chemical calculations to problems in natural products chemistry are highlighted, including the elucidation of natural product structures and determination of reasonable mechanisms for their formation.