Myocardial interstitial fibrosis contributes to left ventricular dysfunction leading to the development of heart failure. Basic research has provided abundant evidence for the cellular and molecular mechanisms behind this lesion and the pathways by which it imparts a detrimental impact on cardiac function. Translation of this knowledge, however, to improved diagnostics and therapeutics for patients with heart failure has not been as robust. This is partly related to the paucity of biomarkers to accurately identify myocardial interstitial fibrosis and to the lack of personalized antifibrotic strategies to treat it in an effective manner. This paper summarizes current knowledge of the mechanisms and detrimental consequences of myocardial interstitial fibrosis, discusses the potential of circulating and imaging biomarkers available to recognize different phenotypes of this lesion and track their clinical evolution, and reviews the currently available and potential future therapies that allow its individualized management in heart failure patients.