Cell and gene therapies hold tremendous promise for treating a range of difficult-to-treat diseases. However, concerns over the safety and efficacy require to be further addressed in order to realize their full potential. Synthetic receptors, a synthetic biology tool that can precisely control the function of therapeutic cells and genetic modules, have been rapidly developed and applied as a powerful solution. Delicately designed and engineered, they can be applied to finetune the therapeutic activities, i.e., to regulate production of dosed, bioactive payloads by sensing and processing user-defined signals or biomarkers. This review provides an overview of diverse synthetic receptor systems being used to reprogram therapeutic cells and their wide applications in biomedical research. With a special focus on four synthetic receptor systems at the forefront, including chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors, we address the generalized strategies to design, construct and improve synthetic receptors. Meanwhile, we also highlight the expanding landscape of therapeutic applications of the synthetic receptor systems as well as current challenges in their clinical translation.