Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. Given the wide spectrum of diseases that contribute to CRS-5, several pathophysiological mechanisms are invoked representing the response of the heart and kidney to the contributing disorder that is ongoing. The nature, duration and the underlying condition of the heart and kidney strongly influence the clinical course of CRS-5. In this paper we discuss the pathophysiology of CRS-5 in the setting of sepsis as a model system for CRS-5 providing a brief overview of strategies for monitoring and therapeutic intervention. We offer a framework for reference for considering other disorders leading to CRS-5 where the development of cardiac and renal dysfunction is more insidious.