Despite ischemic heart disease (IHD) has been commonly identified as the consequence of obstructive coronary artery disease (OCAD), a significant percentage of patients undergoing coronary angiography because of signs and/or symptoms of myocardial ischemia do not have any significant coronary artery stenosis. Several mechanisms other than coronary atherosclerosis, including coronary microvascular dysfunction (CMD), coronary endothelial dysfunction and epicardial coronary vasospasm, can determine myocardial ischemia or even myocardial infarction in the absence of flow-limiting epicardial coronary stenosis, highlighting the need of performing adjunctive diagnostic tests at the time of coronary angiography to achieve a correct diagnosis. This review provides updated evidence of the pathophysiologic mechanisms of myocardial ischemia with non-obstructive coronary arteries, focusing on the diagnostic and therapeutic implications of performing a comprehensive invasive functional evaluation consisting of the assessment of both vasodilation and vasoconstriction disorders. Moreover, performing a comprehensive invasive functional assessment may have important prognostic and therapeutic implications both in patients presenting with myocardial ischemia with non-obstructive coronary arteries (INOCA) or myocardial infarction with non-obstructive coronary arteries (MINOCA), as the implementation of a tailored patient management demonstrated to improve patient’s symptoms and prognosis. However, given the limited knowledge of myocardial ischaemia with non-obstructive coronary arteries, there are no specific therapeutic interventions for these patients, and further research is warranted aiming to elucidate the underlying mechanisms and risk factors and to develop personalized forms of treatment.