How can conformationally restricted polyvalent molecules be accessed rapidly? A sequential approach involving two multiple multicomponent macrocyclizations including bifunctional building blocks (MiBs) with up to five Ugi-four-component reactions (Ugi-4CR) has been developed to produce nonsymmetric macromulticycles. Topologically diverse structures, such as nonsymmetric cryptands and clam-,and igloo-shaped macromulticycles were obtained in reaction sequences that comprise the incorporation of up to 13 building blocks by forming 20 new bonds without purification of intermediates. Cryptands were produced by a sequential-MiB procedure in which the Ugi-type functional groups of the second MiB are attached to the peptoid backbones from the first multicomponent macrocyclization. These macrobicycles show two completely new features; i.e., three different tether chains can be obtained in one pot, and tertiary amide bonds are used as bridgeheads. Alternatively, the same reaction sequence, i.e., MiB/deprotection/MiB, can be used to produce clam-shaped macrobicycles, demonstrated with a tetrafunctional cholanic steroid as a hinge moiety. Macrotetracycles endowed with igloo-type topologies are accessible by an advanced protocol featuring consecutive double and 3-fold Ugi-4CR-based macrocyclizations. Other building blocks than cholanic steroids employed include aryl, heterocyclic, polyether, and other recognition motifs. The examples given are a first-generation demonstration of an "architectural chemistry" that allows to construct three-dimensional multimotif covalent molecular "buildings" of unprecedented complexity by design.