Cardiorenal syndrome represents the confluence of intricate hemodynamic, neurohormonal, and inflammatory pathways that initiate and propagate the maladaptive cross talk between the heart and kidneys. Several of these pathophysiological principles were described in older historical experiments. The last decade has witnessed major efforts in streamlining its definition, clinical phenotypes, and classification to improve diagnostic accuracy and deliver optimal goal-directed medical therapies. The ability to characterize the various facets of cardiorenal syndrome based on its pathophysiology is poised in an exciting vantage point, in the backdrop of several advanced diagnostic strategies, notably cardiorenal biomarkers that may help with accurate delineation of clinical phenotype, prognosis, and delivery of optimal medical therapies in future studies. This promises to help integrate precision medicine into the clinical diagnosis and treatment strategies for cardiorenal syndrome and, through a heightened understanding of its pathophysiology, to deliver appropriate therapies that will reduce its associated morbidity and mortality.