Heart failure continues to be a major global concern. Despite greater understanding of the 'maladaptive' mechanisms that contribute to its development and progression, morbidity and mortality from heart failure remain high. Existing treatment modalities have been hampered by the development of electrolyte abnormalities, diuretic resistance and the cardiorenal syndrome. This review focuses on the pharmacological properties and clinical data of therapeutic agents under investigation that target vasopressin and adenosine receptors for the treatment of patients with heart failure.