Heart failure with a preserved ejection fraction (HFpEF) is increasingly prevalent and a leading cause of morbidity and mortality worldwide. HFpEF has a complex pathophysiology, with recent evidence suggesting that an interaction of cardiovascular and noncardiovascular comorbidities (e.g. obesity, hypertension, diabetes, coronary artery disease, and chronic kidney disease) induces an inflammatory state that eventually leads to myocardial structural and functional alterations. Current ACCF/AHA guidelines suggest incorporation of biomarkers along with clinical and imaging tools to establish the diagnosis and disease severity in heart failure (HF). However, the majority of data on biomarkers relating to their levels, or their role in accurate diagnosis, prognostication, and disease activity, has been derived from studies in undifferentiated HF or HF with a reduced EF (HFrEF). As the understanding of the mechanisms underlying HFpEF continues to evolve, biomarkers reflecting different pathways including neurohormonal activation, myocardial injury, inflammation, and fibrosis have a clinical utility beyond the diagnostic scope. Accordingly, in this review article we describe the various established and novel plasma biomarkers and their emerging value in diagnosis, prognosis, response, and guiding of targeted therapy in patients with HFpEF.