Forefront techniques for molecular interrogation of mammalian tissues, such as multiplexed tissue imaging, intravital microscopy, and single-cell RNA sequencing (scRNAseq), can combine to quantify cell-type abundance, co-localization, and global levels of receptors and their ligands. Nonetheless, it remains challenging to translate these various quantities into a more comprehensive understanding of how cell-cell communication networks dynamically operate. Therefore, construction of computational models for network-level functions - including niche-dependent actions, homeostasis, and multi-scale coordination - will be valuable for productively integrating the battery of experimental approaches. Here, we review recent progress in understanding cell-cell communication networks in tissue. Featured examples include ligand-receptor dissection of immunosuppressive and mitogenic signaling in the tumor microenvironment. As a future direction, we highlight an unmet potential to bridge high-level statistical approaches with low-level physicochemical mechanisms.