Understanding of chronic heart failure (HF) has progressed from the concept of a purely hemodynamic disorder to that of a syndrome that results from dysfunction in interconnected molecular pathways. As a result, the focus of research investigations and clinical care has shifted to measurement and modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers provide a window into the pathophysiology of chronic HF and therefore have important therapeutic implications. However, the use of biomarkers in the treatment of HF remains in its infancy. This is partly a result of shortcomings in research studies and a dearth of biomarker-guided clinical trials. In this review, we summarize the potential therapeutic implications of promising biomarkers that uniquely capture the molecular dysfunction that occurs in chronic HF. We discuss the need for strict statistical standards in biomarker studies, provide an overview of biomarker-guided clinical trial design, and discuss the therapeutic potential of a multimarker-based strategy.