Display omitted Synthetic biology aims to repurpose cells to sense a wide range of input signals and respond by conditionally expressing user-defined output genes. In this review, we highlight the latest developments in synthetic-biology-inspired in vitro and in vivo diagnostics and therapeutics employing engineered mammalian cells. Recent work has led to the creation of modular synthetic receptors with adaptable ligand-binding domains whose recognition specificity can be easily tailored to target various diseases. Engineered cells can now sense a great variety of soluble and surface-bound antigens with unprecedented selectivity and sensitivity, and implanted designer cells equipped with appropriate response modules can successfully treat diabetes, cancer and autoimmune diseases in animal models. Recently, the first immunotherapies using chimeric-antigen receptor (CAR)-T cells were approved to treat lymphoma patients. As this milestone paves the way for translating state-of-the-art synthetic biology approaches into clinical benefit, we also discuss the challenges facing engineered cell therapies.