Improved understanding of the pathophysiology of salt and water homeostasis has provided a foundation for explaining the renal mechanisms of emerging therapies for heart failure, as well as why renal function might potentially be improved or harmed. These aspects are reviewed in this article for a number of newer therapies including adenosine, endothelin, and vasopressin receptor antagonists, as well as extracorporeal ultrafiltration. An appreciation of the complexity and sometimes opposing pathways of these approaches may explain their limited efficacy in early trials, in which there has not been a substantial improvement in patient or renal outcomes. In that there is often a balance between beneficial and maladaptive receptor actions and neurohumoral responses, this physiologic approach also provides insight into the rationale for combining therapies. Multi-agent strategies may thus maximize their effectiveness while minimizing adverse effects and tolerance. In this paper, the theoretical impact of the emerging agents based on their mechanism of action and pathophysiology of the disease is initially addressed. Then, the available clinical evidence for each class of drugs is reviewed with special emphasis on their effect on kidney-related parameters. Finally, a general overview of the complexity of the interpretation of trials is offered along with a number of potential explanations for the observed results.