Coronary angiography (CA) has historically represented the backbone of the diagnostic algorithm of chronic coronary syndromes. Yet, in more than 50 % of patients complaining of anginal-sounding chest pain, CA does not show obstructive coronary artery disease (CAD), nor do functional tests unmask flow-limiting atheroma. The turning point for these patients came with the realization that ischemia (and angina) can exist outside the context of obstructive CAD, i.e. in the absence of visually assessed “significant” luminal stenosis and/or in presence of a negative pressure test.