Acute and Chronic Coronary Syndromes represent two major medical challenges and are the leading cause of cardiovascular mortality and morbidity. While Chronic Coronary Syndrome (CCS) can be defined as the whole group of structural and/or functional abnormalities involving coronary arteries before and after an acute event, Acute Coronary Syndrome (ACS) encompasses the condition of acute myocardial ischemia (with or without consequent myocardial injury and troponin release) due to dynamic mechanisms such as athero-thrombosis or vasospasm. Because of this complex interplay between structural and functional mechanisms arising from both the epicardial and microvascular compartments, a comprehensive approach to fully investigate the whole spectrum of coronary disease is therefore essential. To address this issue, the invasive functional assessment has evolved through the years, from a way to guide revascularization to a meticulous protocol for characterizing ischemia-leading mechanisms and stratifying prognosis both in ACS and CCS. However, coronary physiology remains underused in clinical practice, and multiple gaps in knowledge still exist; on top of this, there is increasing heterogeneity regarding how to perform functional assessment, with different protocols proposed by various centers. The aim of this review is to summarize the evidence in the field of coronary physiology, and to discuss how and when to use it at its best.