H eterocyclic structural architectures occur in many bioactive natural products and synthetic drugs, and these structural unitsserve as important intermediates in organic synthesis. This Account documents our recent progress in the development ofcascade reactions to construct complex carbocycles and heterocycles. We describe the rational design of cascade reactions and indepth investigations of their mechanism as well as their applications in the synthesis of drugs, natural products, and relatedmolecular analogs.