The self-assembly and solid-state structures of host-guest inclusion compounds with lamellar architectures based on a common building block, a resilient hydrogen-bonded sheet consisting of guanidinium ions and sulfonate moieties of organodisulfonate "pillars", are described. The pillars connect adjacent sheets to generate galleries with molecular-scale cavities occupied by guest molecules. The size, shape, and physicochemical character of the inclusion cavities can be systematically adjusted by interchanging framework components while maintaining the lamellar architecture, enabling prediction and control of crystal lattice metrics with a precision that is unusual for "crystal engineering". The reliability of the lamellar architecture is a direct consequence of conformational flexibility exhibited by these hosts that, unlike rigid systems, enables them to achieve optimal packing with guest molecules. The adaptability of these hosts is further reflected by an architectural isomerism that is driven by guest templating during assembly of the inclusion compounds. Host frameworks constructed with various pillars display metric interdependences among specific structural features that reveal a common mechanism by which these soft frameworks adapt to different guests. This unique feature facilitates structure prediction and provides guidance for the design of inclusion compounds based on these hosts.