Although novel therapies have improved outcomes in PCI patients, a sizeable number of patients still remain at high cardiovascular risk for recurrent event. There is therefore an unmet need for novel therapies that can improve clinical outcomes, with an associated satisfactory safety profile. Proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme is a novel lipid-lowering target with a potential to impact high-cardiovascular risk populations including patients with coronary artery disease (CAD), undergoing the percutaneous coronary intervention (PCI). A number of canonical and non-canonical pathways of PCSK9 action, including inflammation and platelet activation, as well as their inhibition, are undergoing intense investigation. Areas covered: This review will discuss the currently available evidence on PCSK9 inhibitors, pathways of PCSK9 enzyme action and results or its inhibition, the potential role of PCSK9 inhibitors in specific populations undergoing PCI, and completed and ongoing studies in patients with CAD. Expert commentary: PCSK9 inhibitors clinical outcomes in high risk cardiovascular disease patients and have the potential to function as powerful adjunctive therapy in patients undergoing PCI by a twofold mechanism on both lipid lowering and platelet/inflammation pathways.