Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence and has no guideline-recommended therapy, related in part to a lack of mechanism. Traditionally, HFpEF was thought to be secondary to afterload overload due to systemic hypertension; however, accumulating evidence suggests that HFpEF continues to worsen despite adequate control of blood pressure. Emerging data support the suggestion that myocardial ischemia secondary to coronary microvascular dysfunction could be the new paradigm pathophysiology. Several prospective, observational cohort studies indicate that the outcomes of patients with microvascular dysfunction, after an interval of several years, are dominated by HFpEF hospitalizations. Further, the most prevalent clinical phenotype (eg older women with multiple comorbidities) of patients with HFpEF resembles those with coronary microvascular dysfunction, albeit older. In this review, we provide in-depth insight about this emerging HFpEF paradigm, discuss potential therapeutic implications of this pathophysiology, and summarize some important knowledge gaps.