Before the percutaneous era, the mortality rate of patients with coronary heart disease not suitable for cardiac surgery was extremely high. This limit has been progressively exceeded with the advent of minimally invasive approaches, which, although initially intended exclusively for low risk scenarios, was then employed in complex patients often too compromised to undergo cardiac surgery. We are currently witnessing, however, a sudden expansion in percutaneous coronary interventions (PCI) in extreme cases, perceived as high-risk by operators, imposing an important burden of human and economic resources on interventional cardiology as a whole. In this review, the literature regarding the current definition of high-risk PCI and its implications has been reviewed. In summary, all proposed definitions of high risk PCI combine features related to three main clinical areas: 1) patient risk factors and comorbidities (incorporating those which preclude surgical or percutaneous revascularization such as diabetes, chronic obstructive pulmonary disease, chronic kidney disease, lung disease, frailty, advanced age); 2) location of the disease and complexity of coronary anatomy (including multi-vessel disease, left main disease, chronic total occlusion, bifurcations); 3) hemodynamic clinical status (ventricular dysfunction, concomitant valvular disease or unstable characteristics). Importantly, encouraging results in terms of efficacy and gains in health status of PCI in (variously defined) high-risk, as compared to the low-risks patients, are reported. Thus, treating high-risk patients is becoming increasingly relevant, to the point that current guidelines now particularly highlight the appropriateness of percutaneous interventions in this setting .