The incidence of cardiac failure and chronic renal failure is increasing and it has now become clear that the co-existence of the two problems has an extremely bad prognosis. We propose the severe cardiorenal syndrome (SCRS), a pathophysiological condition in which combined cardiac and renal dysfunction amplifies progression of failure of the individual organ, so that cardiovascular morbidity and mortality in this patient group is at least an order of magnitude higher than in the general population. Guyton has provided an excellent framework describing the physiological relationships between cardiac output, extracellular fluid volume control, and blood pressure. While this model is also sufficient to understand systemic haemodynamics in combined cardiac and renal failure, not all aspects of the observed accelerated atherosclerosis, structural myocardial changes, and further decline of renal function can be explained. Since increased activity of the renin-angiotensin system, oxidative stress, inflammation, and increased activity of the sympathetic nervous system seem to be cornerstones of the pathophysiology in combined chronic renal disease and heart failure, we have explored the potential interactions between these cardiorenal connectors. As such, the cardiorenal connection is an interactive network with positive feedback loops, which, in our view, forms the basis for the SCRS.