An understanding of the different microbial constellations or microbiomes, which every habitat and every organism harbor, will be the key to addressing many of the challenges humanity will face in the twenty-first century. Such comprehension could launch several innovations relating to natural and cultural capital, including historical and artistic heritage. In relation to cultural heritage, microorganisms are mainly known through their role as deteriogens, but the features creating damage can be exploited positively, attaining more sustainable restoration strategies, in accordance with the principles of compatibility and retreatability deriving from reflections on the Cultural Heritage inspired by the Charter of Venice (International charter for the Conservation and restoration of monument and sites (the Venice Chart 1964). In: ICOMOS, IInd International Congress of Architects and Technicians of Historic Monuments, 1964) onwards. In this article, we show a series of case studies, using both wild-type microorganisms and plant-based extracts, providing a comprehensive proof of concept of the feasibility of biotechnological solutions for a more sustainable restoration strategy, to replace the products in use which are often dangerous for operators, aggressive for works of art and no longer compatible with the environment. The overview of the case studies presented, many of which are still unpublished, responds to the need to go beyond the state of the art and has entirely sprung from suggestions by restorers, interested in learning about potential innovations and strongly determined to introduce non-toxic products in their daily work. In this perspective, the case studies dealt with two topics: bio-cleaning and disinfection. Noteworthy results were obtained on a platform of different types of artworks and different materials with compatible, harmless and selective products. © The Author(s) 2021.