Symptoms and signs of myocardial ischemia are often found in patients with hypertrophic cardiomyopathy (HCM) despite angiographically normal coronary arteries. Myocardial ischemia is deemed responsible for some of the lethal complications of HCM including ventricular arrhythmias, sudden death, progressive left ventricular remodeling, and systolic dysfunction. In the past decade, a number of studies using positron emission tomography have demonstrated severe impairment of the vasodilator response to dipyridamole in the majority of HCM patients, not only in the hypertrophied septum but also in the non-hypertrophied left ventricular free wall. In the absence of coronary stenoses, this finding is indicative of diffuse microvascular dysfunction, in line with the autoptic evidence of widespread abnormalities of the intramural coronary arterioles. In turn, microvascular dysfunction represents a very likely substrate for recurrent ischemia. This may account for the fact that microvascular dysfunction has recently been shown to represent an early and powerful predictor of an unfavorable outcome in HCM. The aim of this article is to provide a concise overview of the available evidence of microvascular dysfunction and ischemia in HCM, and to speculate on the potential implications for management.