- Increases in the volume of the interstitial space are readily recognized clinically as interstitial edema formation in the loose connective tissue of skin, mucosa, and lung. However, the contents and the hydrostatic pressure of this interstitial fluid can be very difficult to determine even in experimental settings. These difficulties have long obscured what we are beginning to appreciate is a dynamic milieu that is subject to both intrinsic and extrinsic regulation. This review examines current concepts regarding regulation of interstitial volume, pressure, and flow and utilizes that background to address three major topics of interest that impact IV fluid administration. The first of these started with the discovery that excess dietary salt can be stored non-osmotically in the interstitial space with minimal impact on vascular volume and pressures. This led to the hypothesis that, along with the kidney, the interstitial space plays an active role in the long-term regulation of blood pressure. Second, it now appears that hypovolemic shock leads to systemic inflammatory response syndrome principally through the entry of digestive enzymes into the intestinal interstitial space and the subsequent progression of enzymes and inflammatory agents through the mesenteric lymphatic system to the general circulation. Lastly, current evidence strongly supports the non-intuitive view that the primary factor leading to inflammatory edema formation is a decrease in interstitial hydrostatic pressure that dramatically increases microvascular filtration.