Protein-based sensors and switches provide attractive tools for the real-time monitoring and control of molecular processes in complex biological environments, with applications ranging from intracellular imaging to the rewiring of signal transduction pathways and molecular diagnostics. A synthetic-biology approach to construct these protein switches from functionally and structurally well-defined protein modules has only recently emerged. This chapter first discusses some of the basic engineering principles that are relevant for the rational design and thermodynamic description of these systems. These principles are subsequently discussed by giving an overview of recent work in this area. The final part of this chapter identifies future opportunities as well as some of the challenges that remain to be addressed to make the construction of protein switches a true engineering discipline.