Natriuretic peptides (NPs) have been discovered for 30 years, and the clinical use of B-type natriuretic peptides (BNP) and N-terminal pro-B type natriuretic peptide (NT-proBNP) precursors have been a landmark in the management of cardiovascular disease, particularly in heart failure. The BNP has a powerful cardioprotective effect, but the BNP that rises dramatically after heart failure does not show corresponding activity, which is known as the “natriuretic peptide paradox”. In recent years, with the use of mass spectrometry and nuclear magnetic resonance techniques, “natriuretic peptide paradox” is being revealed through novel metabolic findings and testing technology. There are many different biologically active BNP isoforms in the peripheral circulation, and BNP metabolism after heart failure is different from that in the physiological state. Although the significant increase of BNP is detected after heart failure, it is essentially false positive due to bottlenecks in conventional the assay reagents of cross-react to various BNP isoforms, and therefore the bioactive levels of BNPs have been overestimated. So, we believe that it is necessary to strengthen the understanding of BNP in different pathophysiological conditions , and establish sensitive and specific detection methods by biochemical means to identify BNP_1-32, BNP_1-30, BNP_3-32 and pro-B-type natriuretic peptide (proBNP). Accurate detection of BNPs will help us understand the deeper pathophysiological mechanisms of heart failure, and make precise clinical decision on the diagnosis and treatment.