The detailed pathophysiology of heart failure with preserved ejection fraction (HF-PEF) remains an area of active research and controversy; however, abnormalities of diastolic function are generally believed to play an important role. Most commonly, diastolic dysfunction occurs as a consequence of myocyte hypertrophy, endomyocardial fibrosis, and abnormalities of intracellular calcium handling that are related to normal myocardial aging and accelerated by comorbidities such as hypertension, diabetes, coronary artery disease, and obesity. In this article, three fundamental risk factors are considered for “secondary” diastolic dysfunction and HF—hypertension, diabetes, and obesity—with an emphasis on the clinical epidemiology, pathophysiologic mechanisms, and treatment implications of each. The article concludes with a brief discussion of “primary” diastolic HF due to infiltrative or restrictive cardiomyopathies.