In 1967 a first case of angina with angiographically normal coronary vessels was described. That same year, exactly 10 years before the first percutaneous coronary intervention (PCI), the first patient with angina and normal coronary angiography was described. Ever since, for nearly 50 years, this clinical entity remains a subject of numerous discussions and studies. (1-3) There are two basic groups of hypothesis to explain the pathophysiological mechanisms of non-obstructive coronary artery disease (CAD): ischemic and non-ischemic groups of hypothesis. Ischemic theory is based on abnormal microvascular function, and non-ischemic theory is based on the changed perception of pain. Ischemic hypothesis includes the factors that may be endothelium-dependent or independent. Non-ischemic hypothesis is divided according to the involvement of the neural system in the afferent and efferent components. In the background of ischemic, endothelium dependent dysfunction are hypertension, diabetes, glucose intolerance, dyslipidemia, smoking, and in the background of endothelium dysfunction independent hypothesis is inflammation, lack of estrogen in women, hysterectomy, insulin resistance. Non-ischemic group consists hypothesis theory of neural disorders which may be afferent-adrenergic or efferent-nociceptive, and theory of habitual disorders (behavioral approach). There is a connection between factors which are displayed in microvascular dysfunction and nonischemic factors. It is believed that repeated episodes of microischemia by fibrosis and less severe prolonged inflammation lead to the development of neural abnormalities on afferent and efferent level. Thus, there are closed circuit that connects pathophysiological microvascular disfunction and neural disorder in non-obstructive CAD.