A prolonged state of left ventricular pressure overload, commonly caused by hypertension and aortic valve disease, promotes remodelling of the myocardium that can progress to heart failure with preserved ejection fraction (HFpEF). In animal models, a major factor driving progression from pressure-overload hypertrophy (POH) to HFpEF is the activation and proliferation of an abnormal fibroblast phenotype that is resistant to apoptosis, degrades normal stromal matrix and is replaced with a fibrotic matrix structure. A similar fibroblast phenotype has been identified in the stroma of solid cancers. This cancer-associated fibroblast drives tumour growth and invasion. The proliferation and expansion of these abnormal fibroblast populations in both HFpEF and cancer contribute to progression of disease. In early-phase clinical trials, chemotherapeutic agents targeting cancer-associated fibroblasts had antitumour properties. In this Perspectives article, we postulate that, because the abnormal fibroblast populations in POH and cancer have identical characteristics, chemotherapeutic agents targeting the POH-related fibroblast might attenuate the development of myocardial fibrosis, a pathophysiological hallmark of HFpEF. These agents must be designed to target the abnormal fibroblasts with high specificity because many classes of chemotherapeutic drugs can themselves cause myocardial dysfunction and heart failure.