For decades we have been testing blood either ex vivo or else placing monitors directly in the bloodstream to "see" what might be going on in tissues. In the last 20 yrs, conceptual and practical advances in interstitial monitoring have begun to challenge traditional approaches. In this review we explore how interstitial monitoring might be used as a platform for future diagnostics and therapy in critical illness. From a diagnostic perspective, interstitial analysis has been instructive about the pathophysiology of critical illness. Valuable insights have been gained into the pathophysiology of critical illness. To this end, examples from the areas of interstitial oxygenation and acid base, endocrine pathophysiology, and head injury monitoring have been used. From a therapeutic perspective, the main focus has been on antibiotic therapy and an improved understanding of pharmacokinetics and pharmacodynamics in critical illness. Monitoring of the interstitium is feasible and can be achieved through minimally invasive techniques. It has improved the understanding of the pathophysiology of critical illness, holds potential in the diagnosis and management of sepsis, may allow early prediction of organ deterioration, and finally offers the possibility of reduction of blood testing and minimizing blood loss. While all of these hold promise, randomized trials will need to be conducted based on interstitial end points rather than plasma end points. This will pave the way for a more rational approach to the therapy of critically ill patients.