Quantum chemical calculations have been used in the development of synthetic methodologies to analyze the reaction mechanisms of the developed reactions. Their ability to estimate chemical reaction pathways, including transition state energies and connected equilibria, has led researchers to embrace their use in predicting unknown reactions. This perspective highlights strategies that leverage quantum chemical calculations for the prediction of reactions in the discovery of new methodologies. Selected examples demonstrate how computation has driven the development of unknown reactions, catalyst design, and the exploration of synthetic routes to complex molecules prior to often laborious, costly, and time-consuming experimental investigations.