The growth and adaptation of microvascular networks are essential processes in development, tissue homeostasis, and responses to disease. The signaling networks and cellular behaviors that underpin the establishment and remodeling of microvessels are complex, dynamic, and spatially heterogeneous. Computational modeling approaches have enabled otherwise intractably difficult experiments to be performed in silico with high throughput hypothesis testing and generation. Computational and mathematical models at nearly every relevant level of biological scale (gene-to-tissue) have offered new insights. Increasingly, multiscale models that bridge phenomena at one level of scale to another, have been created and deployed to understand how perturbations within and around individual cells in a tissue affect vessel structure and overall organization of the network. Close integration with in vitro or in vivo experimental analogs, typically afforded by endothelial cell culture models or various thin vascularized tissues in small animal models (e.g. retina, subcutaneous tissue, ear, thin muscles), facilitates model specification and independent validation. Collaborative partnerships, which are often highly interdisciplinary, have emerged to fuel linkages between different modeling approaches and close coupling of models with experiments. Our group has recently partnered with other modeling groups and with experimental biologists to develop a novel multiscale model of sprouting angiogenesis (Figure 1). We have coupled agent-based modeling (ABM) with receptor-ligand kinetics modeling to explore how signaling inputs from neighboring cells (e.g. NOTCH/Dll4) and extracellular cues (e.g. VEGF) coordinate capillary sprouting and microvascular network patterning. Cellular functions including mitosis, migration, and phenotype regulation are explicitly modeled in the ABM, while a coupled partial differential equations model predicts extracellular gradients of growth factor, as well as membrane-bound and soluble receptor-ligand binding in and around the cell membrane. We demonstrate that when key parameters that are impossible to measure empirically (e.g. extent of the VEGF gradient across the length of a single cell) are varied within certain ranges, our multiscale model can accurately predict locations of capillary sprout emergence from a parent vessel that are consistent with independent experimental observations obtained using the embryoid body model of vasculogenesis. Sensitivity analyses further suggest that initial geometry is key to determining the location of sprout initiation while chemotactic gradients principally govern the rate of sprout extension. As with any model — experimental or computational — the true test of its utility is the ability to uncover new understanding that advances the field. To this end, we are deploying our multiscale model in an iterative model-experiment-model cycle in order to probe the fundamental mechanisms of sprout initiation, extension, maturation, and network patterning in the context of sprouting angiogenesis.