Percutaneous coronary intervention (PCI) of coronary chronic total occlusion (CTO PCI) is one of the most challenging but rewarding procedures in the portfolio of interventional cardiologists. Several challenges, however, still must be overcome and many questions need to be answered. After coronary artery bypass graft (CABG), disease of the conduits and concomitant progression of atherosclerotic disease to CTO of the subtended native coronary vessels are common and associated with onset of new anginal symptoms and worsening of the prognosis. Which is the best strategy for these post-CABG CTOs? Furthermore, what is the role of physiology in the setting of CTO PCI? In the last decades, many researchers tried to demystify the complex maze but technical limitations and the demanding procedure itself, for both the patient and the operator, do not allow extensive investigation of its impact on clinical practice. Can we enhance periprocedural planning of CTO PCI with a more tailored and multidimensional evaluation? Analysis of coronary computed tomography angiography (CCTA) scans is getting more and more incorporated into the clinical routine and training of interventional cardiologists but mainly focuses on structural valvular disease. Nevertheless, with the appropriate expertise, a lot of information can be derived for coronary intervention to improve procedural planning and potentially outcomes. Finally, in the era of drug-eluting stent, is there a place for strategies that minimize metal implantation in the coronaries to further reduce late-onset adverse events in CTO PCI? This approach could be attractive in CTOs due to the higher risk of target vessel failure and revascularization shown in literature but, at the same time, more challenging due to the histological and anatomical complexity of the disease. In this review, we aim to tackle these questions and concomitantly provide a vision of potential future application of new techniques and technology in CTO PCI that could allow further advancement in this field.