Programmable synthetic receptors are a promising tool in cell and gene therapy, enabling precise control of therapeutic cells and genetic modules. These receptors, designed and engineered to detect specific signals or biomarkers, can regulate the production of bioactive payloads, enhancing the safety and efficacy of treatments. This review discusses various synthetic receptor systems, including chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors, which are used to reprogram therapeutic cells and have wide applications in biomedical research. The review highlights the strategies for designing, constructing, and improving synthetic receptors, as well as the challenges in their clinical translation. Synthetic receptors can be categorized into cell-surface and intracellular types, with cell-surface receptors further divided into those that sense soluble and surface-bound ligands. These receptors are engineered to respond to specific signals, enabling precise control of cellular activities. Examples include CARs, which are used in CAR T cell therapy, and synNotch, which can conditionally drive the expression of therapeutic payloads in engineered T cells. Natural signaling-based receptors and orthogonal signaling-based receptors are two main categories of synthetic receptors. Natural signaling-based receptors rewire endogenous pathways to user-defined outputs, while orthogonal signaling-based receptors operate independently of endogenous pathways. Both types have unique advantages and applications in therapeutic and research settings. Soluble ligand-binding receptors and surface ligand-binding receptors differ in their ability to respond to ligands. Soluble receptors are activated by ligand-induced dimerization, while surface receptors require mechanical force from ligand-receptor interactions. These differences influence their use in various therapeutic applications. Partially modular and fully modular synthetic receptors are distinguished by their reconfigurable components. Fully modular receptors, such as synNotch, can execute novel functions without disrupting endogenous pathways. These receptors are crucial for developing next-generation therapies with enhanced specificity and safety. The engineering of synthetic receptors has been facilitated by advances in biotechnology and high-throughput methods. CARs, a well-known synthetic receptor system, have been widely used in clinical settings, demonstrating their potential in treating blood cancers. Recent advancements include the development of SUPRA CAR systems, which allow for precise targeting of tumor antigens and improved safety. Synthetic Notch receptors, derived from the Notch signaling pathway, are used to conditionally express therapeutic payloads in engineered cells. These receptors can be engineered to respond to specific antigens, enhancing the specificity and efficacy of therapies. Overall, synthetic receptors represent a significant advancement in cell and gene therapy, offering precise control over therapeutic activities and addressing challenges in safety and efficacy. Continued research and development are essential to translate these innovations into clinical applications.Programmable synthetic receptors are a promising tool in cell and gene therapy, enabling precise control of therapeutic cells and genetic modules. These receptors, designed and engineered to detect specific signals or biomarkers, can regulate the production of bioactive payloads, enhancing the safety and efficacy of treatments. This review discusses various synthetic receptor systems, including chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors, which are used to reprogram therapeutic cells and have wide applications in biomedical research. The review highlights the strategies for designing, constructing, and improving synthetic receptors, as well as the challenges in their clinical translation. Synthetic receptors can be categorized into cell-surface and intracellular types, with cell-surface receptors further divided into those that sense soluble and surface-bound ligands. These receptors are engineered to respond to specific signals, enabling precise control of cellular activities. Examples include CARs, which are used in CAR T cell therapy, and synNotch, which can conditionally drive the expression of therapeutic payloads in engineered T cells. Natural signaling-based receptors and orthogonal signaling-based receptors are two main categories of synthetic receptors. Natural signaling-based receptors rewire endogenous pathways to user-defined outputs, while orthogonal signaling-based receptors operate independently of endogenous pathways. Both types have unique advantages and applications in therapeutic and research settings. Soluble ligand-binding receptors and surface ligand-binding receptors differ in their ability to respond to ligands. Soluble receptors are activated by ligand-induced dimerization, while surface receptors require mechanical force from ligand-receptor interactions. These differences influence their use in various therapeutic applications. Partially modular and fully modular synthetic receptors are distinguished by their reconfigurable components. Fully modular receptors, such as synNotch, can execute novel functions without disrupting endogenous pathways. These receptors are crucial for developing next-generation therapies with enhanced specificity and safety. The engineering of synthetic receptors has been facilitated by advances in biotechnology and high-throughput methods. CARs, a well-known synthetic receptor system, have been widely used in clinical settings, demonstrating their potential in treating blood cancers. Recent advancements include the development of SUPRA CAR systems, which allow for precise targeting of tumor antigens and improved safety. Synthetic Notch receptors, derived from the Notch signaling pathway, are used to conditionally express therapeutic payloads in engineered cells. These receptors can be engineered to respond to specific antigens, enhancing the specificity and efficacy of therapies. Overall, synthetic receptors represent a significant advancement in cell and gene therapy, offering precise control over therapeutic activities and addressing challenges in safety and efficacy. Continued research and development are essential to translate these innovations into clinical applications.