A hallmark of heart failure is cardiac fibrosis, which, among other things, contributes to diastolic dysfunction by reducing ventricular compliance. We developed a high throughput phenotypic screen to discover inhibitors of cardiac fibrosis. This screen yielded several small molecules that target epigenetic regulatory factors. I will describe our evaluation of one of these compounds in a pre-clinical model of diastolic dysfunction with preserved ejection fraction, and will focus on its genomic and non-genomic molecular mechanisms-of-action. Furthermore, I will discuss the ability of this epigenetic inhibitor to block ‘hidden cardiac fibrosis’, which is below the limit of detection of histological methods, but can be identified employing mass spectrometry and atomic force microscopy. Suppression of hidden cardiac fibrosis through targeted inhibition of an epigenetic regulator provides a powerful means of preventing and reversing diastolic dysfunction.