In the adult, angiogenesis leads to an expanded microvascular network as new vessel segments are added to an existing microcirculation(1). This necessarily means that growing neovessels must navigate through tissue stroma as they locate and grow towards other neovessels and/or existing vessels of the parent network. We have a growing body of evidence demonstrating that angiogenic neovessels reciprocally interact with the stromal environment (interstitial matrix and stromal cells) resulting in persistent and directed neovascular growth during angiogenesis(2-4). Given the malleability of matrix elements and the viscoelastic properties of collagen gels, neovessel guidance by the stroma is likely due to perpendicular compressive forces arising from active tissue deformation. These similar stromal influences can also control the final network topology of the new microcirculation, including the distribution of arterioles, capillaries and venules(5). In this case, stromal-derived stimuli must be present during the post-angiogenesis remodeling and maturation phases of neovascularization in order to have this effect. Interestingly, the pre-existing organization of vessels prior to the start of angiogenesis has no lasting influence on the final, new network architecture. Additionally, we have new evidence that tissue stromal cells enable the invasion of growing neovessels across interstitial matrix interfaces during angiogenesis through a paracrine-dependent process. Importantly, stromal cells need to be spatially near the growing neovessels suggesting a local, but as of yet undefined, interaction. Combined, the evidence describes interplay between angiogenic neovessels and stroma that is important in directed neovessel growth and invasion. This dynamic is also likely a mechanism by which global tissue forces influence vascular form and function.