The Diels-Alder reaction provides a general and facile entry for the synthesis of six-membered cyclic structures. Consequently, it has been used extensively by organic chemists for the construction of complex compounds with pharmaceutical potential. Nature also appears to have utilized this reaction in the biosynthesis of several secondary metabolites. Given its utility, various catalysts have been discovered for the reaction ranging from simple Lewis acidic transition metals to complex catalytic antibodies. More recently, modified RNA has also been shown to be an effective Diels-Alderase with a highly specific active site. The RNA Diels-Alderase activity was also shown to be absolutely dependent on the nature of the base modification and the presence of cupric ion. Together, these results suggest that this RNA Diels-Alderase achieves a portion of its rate acceleration through Lewis acid catalysis, a different mechanistic mode than similar protein Diels-Alderases. The notion that RNA can accelerate reactions through Lewis acid catalysis suggests that modified RNA may serve as a tunable catalytic platform for the creation of structurally diverse compounds using a variety of powerful chemical transformations.