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Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) is the last frontier in coronary intervention. PCI of CTO carries multiple advantages, such as significant improvement in symptoms, improvement in abnormal wall motion and left ventricular function and, possibly, increased long-term survival. As of today the procedural success is markedly improved because of technical innovations and is limited to highly experienced operators. To enhance the overall success rate from a worldwide perspective, a thorough understanding of its pathophysiology is critical to further development of newer techniques and technologies. In this review, the author outlines in-depth the evidence that underpins our understanding of CTO pathophysiology and its insight into CTO intervention that incorporates various steps and techniques to cross the lesion. Keywords: Chronic total occlusion, Pathophysiology, Percutaneous coronary intervention