Over the past three decades, ischaemia research has been the cornerstone of the management and treatment of patients with atherosclerotic CAD. A robust body of evidence, including non-randomized and randomized trials, has supported the use of invasive and non-invasive coronary function tests to guide coronary revascularization. However, more recent data have questioned the clinical benefits of adopting this approach, especially in patients admitted with acute myocardial infarction. The increasing use of intracoronary imaging has identified the morphological features of plaques at higher risk of causing subsequent acute coronary events, despite the fact that they were not obstructive at the time of the index investigation. However, although functional assessment does not appear to have the same potential for identifying high-risk plaques as imaging modalities, it offers the simplicity and reproducibility of plaque assessment as a unique advantage. Furthermore, the ideal approach for the treatment of the so-called vulnerable plaques is still far from being identified, while a robust body of evidence supports the role of functionally guided revascularization, especially in stable patients. Overall, ischaemia research still provides non-negligible information that contributes to a personalized approach to improve patient outcomes.