Cardiorenal syndromes have been categorized into 5 clinical subtypes based on which organ is perceived to be the primary precipitant of the vicious and interrelated cycle of declining function in both organs. This clinical classification has broadened interest in cardiorenal interactions, but it is merely descriptive, does not rely on or inform predominant pathophysiology, and has produced little change in either practice or the research agenda. In contrast, recent scientific work identifies common pathophysiological pathways for several categories of cardiorenal syndromes, suggesting a unifying pathogenesis. Fibrosis is a common consequence of inflammation- and oxidative stress–related endothelial dysfunction in aging, hypertension, diabetes mellitus, obesity, ischemia, and organ injury. It is a common feature in heart failure and chronic kidney disease. Therefore, we suggest that fibrosis may be not only a marker but also the primary driver of pathophysiology in several cardiorenal syndromes. Interstitial fibrosis in the heart, large arteries, and kidneys may play a key role in the pathophysiology of the cardiorenal syndrome continuum. Focusing on fibrosis as a disease mediator might enable the identification of fibrosis-related biotargets that could potentially be modulated with renin-angiotensin-aldosterone system inhibitors, mineralocorticoid receptor antagonists, or other novel antifibrotic agents in development. This conceptual approach may be an effective new strategy for the prevention and treatment of fibrosis within the cardiorenal syndrome continuum.