Within a tissue, a cell’s position is critically linked to its fate. How does a cell determine its position relative to other cells? In developing tissues, this problem is partly solved by a group of secreted signaling molecules called morphogens. Morphogens move through the extracellular space and establish concentration gradients, acting like a GPS system. However, the capability to provide positional information is not a unique privilege of morphogens. Cells constantly secrete a wide range of metabolites, small peptides, proteins, and vesicles into the extracellular space. Circulating drugs, antibodies and hormones also constantly enter solid tissues. Their distribution is critical for the spatial organization of cell types and states in healthy and diseased tissues, and affects the therapeutic efficacy. We previously discovered that confluently cultured fibroblast cells can communicate over long distances by establishing morphogen gradients in a petri dish (Li et al., 2018; Kim et al., 2020). Taking advantage of this observation, we are reconstituting diverse cell-cell communication systems that are amenable to high-resolution imaging and high-throughput genetic perturbation, to quantitatively understand how cells modulate and decode positional information. We are also asking how the natural diversity of extracellular environments in different organs and tumors modulates cell-cell communication.