Routine and reliable syntheses of self-assembled hybrid materials with tuneable functionalities are urgently required if novel functional nanostructures are to be developed for real-life applications and economic commercialization. This Highlight presents an overview of recent progress in the synthesis and use of a new class of mesolamellar magnesium organophyllosilicate clays containing covalently linked organic functionalities. We focus in particular on strategies of template-directed synthesis, exfoliation, fractionation and re-assembly involving aminopropyl-functionalized organoclays, and illustrate how combinations of these approaches can be used for the fabrication of novel functional hybrid materials with complex morphological form and structure. Examples of mesolamellar intercalation of functional biomolecules such as enzymes, DNA and drugs, nanoscale wrapping of isolated proteins, enzymes and polynucleotides, and engineering of photoactive cell membrane/organoclay superstructures are presented.