The discovery of ANP many years ago sparked interest in the use of natriuretic peptides to diagnose and treat heart failure and other salt-retaining disorders. Since then, there have been successes and failures. A more comprehensive understanding of the natriuretic peptide system, including the role of noncardiac factors such as race/ethnicity, may encourage more targeted approaches. One of the original insights of de Bold et al, was that the heart is an endocrine organ. Endocrine therapies are administered to individuals with specific evidence of endocrine dysfunction, not to capture short-term beneficial effects. For instance, thyroid hormone is given only to patients in whom hypothyroidism is demonstrated, not based on its metabolic actions. Studies are warranted to determine whether a similar strategy for the heart’s endocrine system can advance the prevention and treatment of cardiometabolic disease. CMRU is strategically positioned to advance research toward this important strategic goal.