Cardiorenal syndrome is a focus of interest in heart failure because of the substantial associated morbidity and mortality. Recent clinical trials of novel heart failure therapies targeting the interdependence of cardiac and renal dysfunction have failed to show significant benefits with respect to many end points. The heterogeneity of this patient population and the lack of standardized clinical trial end points complicate forward progress. This article reviews the end points evaluated in key clinical trials of cardiorenal syndrome and synthesizes recent discussions about the appropriateness of end points for future trials.