Although the physics of interstitial fluid balance is relatively well understood, clinical options for the treatment of edema, the accumulation of fluid in the interstitium, are limited. Two related reasons for this failure can be identified. First, the processes involved in the transfer of fluid and proteins into the interstitium from the microvasculature, and their transfer out of the interstitium via the lymphatic system, are governed by complex equations that are not amenable to manipulation by physiologists. Second, the fundamental processes involved include complex anatomical structures that are not amenable to characterization by engineers. The dual tools of the batwing model and simplified mathematical modeling can be used to address the main objective: to integrate microvascular, interstitial, and lymphatic function to determine the effect of their interaction on interstitial fluid volume. In order to address this objective and the limitations of the current state of knowledge of the field, three specific aims were achieved. 1) Develop a simple, transparent, and general algebraic approach that predicts interstitial fluid pressure, volume and protein concentration resulting from the interaction of microvascular, interstitial and lymphatic function. These algebraic solutions provide a novel characterization of interstitial fluid pressure as a balance point between the two processes that determine interstitial inflow and outflow. 2) Develop a simple, algebraic formulation of Edemagenic Gain (the change in interstitial fluid volume resulting from changes in effective microvascular driving pressure) in terms of microvascular, interstitial and lymphatic structural parameters. By separating the structural parameters from functional variables, this novel approach indicates how these critical parameters interact to determine the tendency to form edema. 3) To expand the list of known interactions of microvascular, interstitial, and lymphatic functions to include the direct interaction of venular and lymphatic function. Venomotion was found not only to extrinsically pump lymph but also to mechanically trigger intrinsic lymphatic contractions. These three advances together represent a new direction in the field of interstitial fluid balance, and could only be possible by taking an interdisciplinary approach integrating physiology and engineering.