Nature's repertoire of biosynthetic transformations has recently been recognized to include the Diels–Alder cycloaddition reaction. Evidence now exists that there are enzymes that mediate the Diels–Alder reaction in secondary metabolic biosynthetic pathways. 2002 marked the 100th anniversary of Alder's birth and 75 years since the discovery of the Diels–Alder reaction. It would appear that living systems discovered and made use of this ubiquitously useful ring-forming reaction eons ago for the construction of complex natural products. In this Review an overview is given of all of the known classes of natural products (polyketides, isoprenoids, phenylpropanoids, alkaloids) that have been speculated to arise by a biological Diels–Alder reaction.