At an amazing pace, synthetic biology, bio-informatics and systems biology are expanding the applications of industrial biotechnology contributing to the transition towards a bio-economy due to economic and ecological advantages. Additionally, new-to-nature compounds have been commercialized using biotechnology, showing its enormous potential. Despite these recent advances, the complexity of the microbial metabolism still hampers the transformation of wild type organisms into highly efficient microbial cell factories. To overcome this hurdle, transcriptional biosensors have the potential to become a key enabling tool in synthetic biology and metabolic engineering. The repertoire of industrially useful biosensors is however still lacking and their true potential has not been fully characterized. A better understanding in the development of new-to-nature biosensors will be pursued through novel strategies and engineering principles to obtain portable and orthogonal biosensor parts with defined specificity and response. The process of biosensor-driven optimization of microbial cell factories will be applied to the production of partially acetylated chitooligoasccharides (paCOS) as proof of concept. These molecules are rising in popularity due to their numerous applications in healthcare, pharma, feed and food sectors.