A summary of the development and initial studies on the scope of a powerful tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles is detailed and provides the foundation for its subsequent use in organic synthesis. Implemented with substrates in which both the initiating dienophile and subsequent dipolarophile are tethered to the 1,3,4-oxadiazoles, the studies expanded the scope of oxadiazoles that participate in the reaction cascade, permitted the use of differentiated dienophiles and dipolarophiles, extended their use to unsymmetrical dienophiles and dipolarophiles, provided exclusive control of the cycloaddition regioselectivities, and imposed exquisite control on the cycloaddition stereochemistry. As key reactivity and stereochemical features of the reactions were being defined, the cascade cycloaddition reaction was implemented in the total synthesis of a series of alkaloids including (-)-vindoline, (-)-vindorosine, the closely related natural products (+)-4-desacetoxyvindoline and (+)-4-desacetoxyvindorosine, natural minovine, (+)-N-methylaspidospermidine, (+)-spegazzinine, (-)-aspidospermine, and a number of key analogues. Most recently, it was used in the divergent total syntheses of (+)-fendleridine, (-)-kopsinine, (-)-kopsifoline D, and (-)-deoxoapodine, in which four different strategic bonds in four different classes of the hexacyclic alkaloids were formed from a common cascade cycloaddition intermediate. A large number of vindoline analogues were prepared by variations on the cascade cycloaddition reaction for single step incorporation into analogues of vinblastine. These structural changes to vindoline permitted both systematic alterations to the peripheral substituents as well as deep-seated changes to the core structure and embedded functionality of vinblastine not previously accessible. Although explored initially for accessing vindoline and vinblastine, the use of the cycloaddition cascade in the total synthesis of an impressive range of additional natural products illustrate the power of the methodology. Alternative tethering strategies for the cascade cycloaddition reaction, combined intramolecular and intermolecular variants of either the initiating Diels-Alder reaction or the subsequent carbonyl ylide 1,3-dipolar cycloaddition, an expanded examination of the tethered dipolarophile scope, and applications to additional natural product classes represent attractive areas for future work.