Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide, presenting with acute and chronic coronary syndromes. Although coronary atherosclerosis is a major cause of IHD, many patients with angina or myocardial ischemia do not have obstructive coronary heart disease and impairment of the coronary microcirculation has been increasingly implicated as a relevant cause of IHD. Therefore, coronary microvascular dysfunction (CMD) refers to a term covering a wide spectrum of structural and functional alterations which affect the coronary microcirculation leading to myocardial ischemia and angina. The advent of non-invasive and invasive functional tests has exponentially broadened the ability to recognize CMD and delineate related clinical and biochemical features. Despite major advances in diagnosing and stratifying this condition, therapeutic strategies remain limited and poorly defined. In this review, we will provide an overview of the pathophysiology and the diagnostic evaluation of CMD across the spectrum of cardiovascular diseases. Furthermore, we will discuss the novel therapeutic strategies available for these patients in the perspective of a personalized medicine approach.