Coronary artery disease and atherothrombosis are complex pathologic entities. The intricate interplay between anatomical, cellular and molecular factors characterizes their pathogenesis and determines their clinical manifestations. Coronary artery revascularization strategies, by restoring myocardial blood perfusion, only partially treat ischemic heart disease in its complexity. Pharmacological therapies targeting molecular and cellular components involved in the pathophysiology of atherothrombosis are mandatory in order to prevent cardiovascular complications during and after revascularization and therefore improve clinical outcomes. The developments of antithrombotic pharmacotherapies occurred as a result of an improved understanding of the mechanisms underlying atherothrombotic disease. Unfortunately, the optimal antithrombotic therapy, in both acute and chronic settings, often set significant challenges in daily practice. The main objective of optimal antithrombotic therapies, targeting coagulation factors or the platelet system, is to maximize the anti-thrombotic efficacy while minimizing the bleeding risk. The subtle balance between ischemic and bleeding risk is a complex clinical conundrum that involves pharmacologic factors, the clinical phenotype of coronary artery disease and patient's clinical comorbidities. In a contemporary era, in which a broad armamentarium of pharmacologic agents and diagnostic tools are available, physician practice should shift toward a progressively more customized patient care. For this purpose, selection of the optimal acute and chronic percutaneous coronary intervention (PCI) pharmacotherapy, in terms of potency, duration and adherence, cannot disregard an individualized and careful evaluation of the patient's ischemic and hemorrhagic risk. It is within this context that in the present review article we sought to expose the current topics of debate and controversies in acute and chronic anticoagulant and antiplatelet therapies in patients undergoing PCI.