Many patients with angina or evidence of myocardial ischemia on noninvasive tests have no obstructive coronary artery disease. Ischemia with non-obstructive coronary arteries (INOCA) has been underrecognized despite its association with poor quality of life and effect on cardiovascular events. Two major mechanisms, coronary microvascular dysfunction (CMD) and coronary vasospasm, are keys to INOCA pathophysiology. Although noninvasive tests, such as stress echocardiography, cardiac positron emission tomography, and cardiac magnetic resonance imaging, offer evidence of CMD, the gold standard for diagnosing INOCA is coronary angiography with a comprehensive physiological assessment and provocation test of coronary vasospasm. Here, we provide the etiology and pathophysiology of INOCA and guide for the diagnostic approach and treatment of INOCA.