Synthetic biology approaches living systems with an engineering perspective and promises to deliver solutions to global challenges in healthcare and sustainability. A critical component is the design of biomolecular circuits with programmable input–output behaviors. Such circuits typically rely on a sensor module that recognizes molecular inputs, which is coupled to a functional output via protein-level circuits or regulating the expression of a target gene. While gene expression outputs can be customized relatively easily by exchanging the target genes, sensing new inputs is a major limitation. There is a limited repertoire of sensors found in nature, and there are often difficulties with interfacing them with engineered circuits. Computational protein design could be a key enabling technology to address these challenges, as it allows for the engineering of modular and tunable sensors that can be tailored to the circuit’s application. In this article, we review recent computational approaches to design protein-based sensors for small-molecule inputs with particular focus on those based on the widely used Rosetta software suite. Furthermore, we review mechanisms that have been harnessed to couple ligand inputs to functional outputs. Based on recent literature, we illustrate how the combination of protein design and synthetic biology enables new sensors for diverse applications ranging from biomedicine to metabolic engineering. We conclude with a perspective on how strategies to address frontiers in protein design and cellular circuit design may enable the next generation of sense-response networks, which may increasingly be assembled fromde novocomponents to display diverse and engineerable input-output behaviors.