Proteins that switch between distinct conformational states are ideal to monitor and control molecular processes within the complexity of living cells. Inspired by the modular design of natural signaling proteins, we are pursuing a true engineering approach towards the development of protein switches which we call ‘plug-and-play’ protein engineering. In this approach we explore generic strategies to translate molecular recognition in an input protein domain directly into a readable signal generated by an output protein domain.A comprehensive research program is proposed that explores 4 new design concepts for protein switches:1. FRET 3.0. A generic design concept for genetically encoded fluorescent sensors that does not depend on ligand-induced conformational changes in a receptor domain.2. FRET-bodies. Integration of FRET sensors and antibody technology. Libraries of FRET sensor proteins displaying CDR3-type loops on the donor and acceptor domains are displayed on yeast, allowing efficient high-throughput screening using FACS.3. ELISA in solution. An innovative and generic approach to translate antibody binding directly into an enzymatic activation step is proposed that takes advantage of the unique structural properties of antibodies4. Light-responsive protein switches. Ligand binding proteins will be developed whose affinity can be reversibly controlled by photoresponsive protein domains.An integral aspect of the research program is to combine rational design and directed evolution. Apart from developing generic engineering concepts for specific application areas, modeling tools will be developed that allow quantitative analysis and prediction of conformational stabilities for modular protein switches. The availability of these robust and generally applicable engineering strategies will proof beneficial to many areas of life sciences, providing essential tools for intracellular imaging, synthetic biology, and molecular diagnostics.