The management and control of tissue fluid balance depends on the highly regulated orchestration of various interstitial factors. In particular, lymphatic function, lymphatic biology, and development (lymphangiogenesis), and the extracellular matrix all contribute to interstitial fluid balance. In light of the dynamic interdependence of these factors, our lab has been working towards establishing a mechanical-molecular picture of the process of lymphangiogenesis-that is, bridging the physiological context of lymphangiogenesis with its molecular regulation by studying the coordination of mechanical forces, ECM development, lymphatic biology, and lymphatic capillary organization and development. Our working hypothesis is that the physiological driving force for lymphangiogenesis is the need for organized interstitial fluid flow. This paper will outline the rationale and background for such an approach and highlight some of the recently published findings of our lab and others that support this concept.