The natriuretic peptides are important tools to establish diagnosis and prognosis in heart failure (HF). With application of therapies for HF, changes in both B-type natriuretic peptide (BNP) and its amino terminal cleavage fragment (NT-proBNP) parallel the benefits of the HF therapy applied. This dynamic nature of BNP and NT-proBNP relative to therapeutic intervention in HF has led to the concept of using the biomarkers as a 'guide' for intensification of HF care with a goal of not only achieving guideline-directed medical therapy goals accompanied by targeted natriuretic peptide suppression below prognostic thresholds. In studies achieving this combination of therapy optimization and BNP/NT-proBNP suppression, superior outcomes have been observed, and the approach was well tolerated. Natriuretic peptide-guided HF therapy has recently been given a recommendation in US HF guidelines to achieve guideline-directed medical therapy (Class IIa) and possibly improve outcome (Class IIb), while other clinical practice guidelines (including those from the European Society of Cardiology) await results from emerging clinical trial data. We will review lessons learned in the past regarding this novel concept of biomarker guided HF care, and discuss future directions for the approach.