Patients with angina, evidence of myocardial ischemia and angiography with no obstructed coronary arteries represent a real diagnostic challenge to the clinical cardiologist. Recent evidence has shown that this entity is not as benign as it was thought. Cardiac syndrome X, currently known as myocardial Ischemia with No Obstructed Coronary Arteries (INOCA), has focused predominantly in microvascular dysfunction. However, the other causal mechanisms, such as concealed atherosclerotic coronary artery disease, epicardial coronary spasm and the sensitive heart syndrome, should always be considered. This evidence-based review of the last 20 years of publications raises a practical vision of INOCA syndrome. It approaches the concerns and efforts of investigators who study this syndrome to achieve a proper diagnostic protocol, in order to guide a more appropriate treatment approach according to the predominant pathophysiologic mechanism.