Initially, the renal resistive index (RRI) was investigated with the aim of improving diagnosis in kidney diseases, but this goal was not met. Recently, many papers have highlighted the prognostic significance of the RRI in chronic kidney disease: specifically, in estimating the revascularization success of renal artery stenoses or the evolution of the graft and the recipients in renal transplantation. Moreover, the RRI has become significant in the prediction of acute kidney injury in critically ill patients. Studies in renal pathology have revealed correlations of this index with parameters of systemic circulation. The theoretical and experimental premises of this connection were then reconsidered, and studies analyzing the link between RRI and arterial stiffness, central and peripheral pressure, and left ventricular flow were conducted with this purpose. Many data currently indicate that RRI is influenced more by pulse pressure and vascular compliance than by renal vascular resistance—assuming that RRI reflects the complex interplay between systemic circulation and renal microcirculation and should be considered a marker of systemic cardiovascular risk beyond its prognostic relevance for kidney disease. In this review, we overview the clinical research that reveals the implications of RRI in renal and cardiovascular disease.