The combination of chronic kidney disease (CKD) and heart failure (HF) is associated with an adverse prognosis. Although clinical studies hint at a specific bidirectional interaction between HF and CKD, insight into the pathogenesis of cardiorenal syndrome (CRS) remains limited. We review available evidence on cardiorenal interactions from animal models of CKD and HF and discuss several studies that employed a "double-hit" model to research organ cross talk between the heart and kidneys. Regarding cardiac changes in CKD models, parameters of cardiac remodeling are equivocal and cardiac systolic function generally remains preserved. Structural changes include hypertrophy, fibrosis, and microvasculopathy. In models of HF, data on renal pathology are mostly limited to functional hemodynamic changes. Most double-hit models were unable to show that combined renal and cardiac injury induces additive damage to both organs, perhaps because of the short study duration or absence of organ failure. Because of this lack of "dual-failure" models, we have developed two rat models of combined CKD and HF in which renal dysfunction induced by a subtotal nephrectomy preceded cardiac dysfunction. Cardiac dysfunction was induced either functionally by nitric oxide depletion or structurally by myocardial infarction. In both models, we found that cardiac remodeling and failure were worse in CKD rats compared with controls undergoing the same cardiac insult. Variables of renal damage, like glomerulosclerosis and proteinuria, were also further worsened by combined cardiorenal injury. These studies show that target organ cross talk does occur in CRS. These models may be useful for interventional studies in rats.