Heart failure with preserved ejection fraction (HFpEF) encompasses nearly half of heart failure (HF) worldwide, and still remains a poor prognostic indicator. It commonly coexists in patients with vascular disease and needs to be recognized and managed appropriately to reduce morbidity and mortality. Due to the heterogeneity of HFpEF as a disease process, targeted pharmacotherapy to this date has not shown a survival benefit among this population. This article serves as a comprehensive historical review focusing on the management of HFpEF by reviewing past, present, and future randomized controlled trials that attempt to uncover a therapeutic value. With a paradigm shift in the pathophysiology of HFpEF as an inflammatory, neurohormonal, and interstitial process, a phenotypic approach has increased in popularity focusing on the treatment of HFpEF as a systemic disease. This article also addresses common comorbidities associated with HFpEF as well as current and ongoing clinical trials looking to further elucidate such links.