Crystalline clathrates formed from two-dimensional guanidinium sulfonate hydrogen-bonded networks connected by 4,4'-biphenyldisulfonate "pillars" in the third dimension exhibit a "brick-like" molecular framework that is a predictable architectural isomer of a previously observed bilayer architecture based on the same pillars. The amount of void space in the brick framework is nominally twice that of the bilayer form, with the framework occupying only 30% of the total volume. The formation of the brick architecture can be attributed to steric templating by the included molecular guests and host-guest interactions that favor assembly of this framework over its bilayer counterpart. The brick framework conforms to the different steric demands and occupancies of various aromatic guests (1,4-dibromobenzene, 1-nitronaphthalene, nitrobenzene, and 1,4-divinylbenzene) by puckering of the flexible, yet resilient, hydrogen-bonded network and by rotation of the pillars about their long axes, the latter also governing the width of the pores in the framework. These observations demonstrate that cystal engineering, and the ability to direct architectural isomerism in porous molecular lattices by the appropriate choice of molecular guest, is simplified by the use of robust 2-D networks.