Eight examples of biosynthetic pathways wherein a natural enzyme has been identified and claimed to function as a catalyst for the [4 + 2] cycloaddition reaction, namely, Diels-Alderases, are briefly reviewed. These are discussed in the context of the mechanistic challenges associated with the technical difficulty of proving that the net formal [4 + 2] cycloaddition under study indeed proceeds through a synchronous mechanism and that the putative biosynthetic enzyme deploys the pericyclic transition state required for a Diels-Alder cycloaddition reaction.