High-risk coronary plaque refers to a distinct set of plaque characteristics prone to future coronary events. Coronary physiology represents a group of indexes reflective of the local physiological environment and hemodynamic changes in the macrovascular and microvascular system. Although a large body of evidence has supported the clinical relevance of these 2 factors, currently, identifying plaque morphology cannot reliably capture the lesion subset that causes hard events. Also, the guideline-directed approach based on physiological indexes cannot fully predict and prevent clinical events. In parallel, there is accumulating evidence that these 2 aspects of coronary artery disease influence each other with significant clinical implications, despite traditionally being considered to have separate effects on significances, treatments, and outcomes. In this state-of-the-art review, the authors explore the clinical evidence of pathophysiological interplay of physiological indexes related to local hemodynamics, epicardial stenosis, and microvascular dysfunction with plaque morphological characteristics that provide a better understanding of the nature of coronary events. Furthermore, the authors examine the emerging data on the complementary role between plaque morphology and coronary physiology in prognostication and how to apply this concept to overcome the limitations of individual assessment alone. Finally, they propose the potential benefit of integrative assessment of coronary anatomy, plaque quantity and quality, and physiological aspects of a target lesion and vessels for personalized risk profiling and optimized treatment strategy.