Recent studies on enzymes catalyzing the Diels-Alder reaction, often named "Diels-Alderases", clearly demonstrated the involvement of this synthetically useful reaction in the biosynthesis of natural products. This review covers natural Diels-Alder type cycloadducts, synthetic efforts on the chemical feasibility of the biosynthetic Diels-Alder reaction and a brief history of studies on Diels-Alderases. In addition, reaction mechanisms of artificial and natural Diels-Alderases are discussed.