Abstract. Synthetic biology combines biological and engineering principles to regulate cellular processes, and is emerging as an important area of biomedical research. To date, synthetic biology has focused largely on manipulating processes inside cells, most notably to control gene expression or metabolism, and arranging them into modules that perform discrete functions. By contrast, current cell- culture based synthetic approaches are ill-equipped to manipulate processes that control interactions between cells to create desired outcomes at the tissue level, a capacity that would be of particular value in the fields of tissue engineering and regenerative medicine. What is needed is a genetically tractable in vivo platform within which synthetic cell-cell signaling tools can be rapidly created, tested, optimized and diversified, before they are deployed and further refined in systems that have therapeutic and biotechnological applications. We propose to fulfill this requirement by establishing a Drosophila system for designing synthetic intercellular signaling that controls tissue behavior. We have developed prototype synthetic ligand/receptor systems predicated on the basic mechanism of Notch activation, where mechanical force exerted by ligand endocytosis induces the cleavage of an extracellular “force-sensitive” domain of the receptor. We have paired our synthetic receptors with a new genetic protocol for controlling ligand/receptor interactions, conducting functional screens and altering synthetic receptor outputs. First, we will diversify our repertoire of synthetic receptors by conducting a large-scale screen for new heterologous force-sensitive cleavage domains. Second, we will rigorously assess our new receptors for their suitability to be used in circuits and characterize their important response parameters, such as the potency of signal and capacity for regulation. Last, we will assemble circuits of synthetic signaling modules to produce predictable outputs within an epithelial tissue. If successful, the proposed experiments will be a significant step toward our long-term goal of establishing a tractable in vivo system for developing cell-cell signaling technology that has future applications in tissue engineering and regenerative medicine.