The fundamental study of the biogenetic origin of natural products has always been limited from the experimental point of view because proposed reaction mechanisms have only been supported on the molecular structures of reagents and the reaction products. In a seminal contribution, Ortega and Maldonado (Ortega, A.; Maldonado, E. Heterocycles, 1989, 29, 635−638.) described an experiment relevant for the development of the biogenetic theory of sesquiterpene lactones. They were able to obtain the one-pot transformation of a pseudoguaianolide sesquiterpenic lactone from a germacranolide using bentonitic earth as the catalyst. This transformation involved two steps in the biogenesis of these compounds (germacranolide → guaianolide → pseudoguaianolide) and is significant because when Brönsted or Lewis acids are used, it is only possible to isolate the product of the next step of the biogenesis. The results presented here support the biogenetic theories by Hendrickson and Fischer and question the concerted nature of the Herz proposal. Some questions about the mechanisms still remain unanswered; mainly because it was only possible to isolate a few stable byproducts. Using the third generation functional mPWB95 developed by Truhlar, it was possible to study the mechanisms associated with the biogenesis of pseudoguaiananolides. Its application can explain the origin of all the byproducts obtained in the original experiment and establish the validity of the original biogenetic hypothesis. The performance of the above-mentioned functional was compared to B3LYP, B97−2, and B1B95 functionals and the MP2 method, finding that mPWB95 competes successfully with all the latter in both, the determination of the magnitude of the activation energies and the ability to map the potential energy surface. Therefore, the mPWB95 method can be considered good to deal with this type of study.