Diatom frustules represent one of the most complex examples of micro- and nano-structured materials found in nature, being the result of a biomineralization process refined through tens of milions of years of evolution. They are constituted by an intricate, ordered porous silica matrix which recently found several applications in optoelectronics, sensing, solar light harvesting, filtering, and drug delivery, to name a few. The possibility to modify the composition and the structure of frustules can further broaden the range of potential applications, adding new functions and active features to the material. In the present work the most remarkable physical and chemical techniques aimed at frustule modification are reviewed, also examining the most recent genetic techniques developed for its controlled morphological mutation.