Antiplatelet agents have a central role in the treatment and prevention of ischemic events in patients with coronary artery disease (CAD), including primary prevention, chronic coronary syndrome (CCS), and acute coronary syndrome (ACS). Although the evidence on primary prevention originally favored routine aspirin administration, subsequent research showed that aspirin should be given only to selected patients between 40 and 70 years of age, while routine administration can be detrimental due to increased bleeding. Current data in CCS patients largely support the use of long-term antiplatelet agents, as these patients greatly benefit from such a secondary prevention approach, with both aspirin and clopidogrel showing significant reduction in long-term major adverse cardiovascular events (MACE). In case of elective percutaneous coronary intervention, dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel for 6 months has been shown to be the antiplatelet regimen of choice, as it provides the best balance between MACE prevention and avoidance of increased bleeding, although DAPT duration and selection of P2Y12 inhibitor can be modulated according to the patient’s specific ischemic and bleeding risks. In ACS patients, current evidence supports the administration of more intense DAPT regimens, due to the intrinsic higher ischemic risk of this condition. Therefore, DAPT with either ticagrelor or prasugrel in addition to aspirin for up to 12 months is the current standard of care. However, DAPT intensity can be modulated (i.e., de-escalation) in patients at high bleeding risk. De-escalation can occur by either shortening DAPT duration (e.g., withdrawing either aspirin or the P2Y12 inhibitor), reducing the dose of the P2Y12 inhibitor, or switching to clopidogrel. DAPT can also be prolonged beyond 12 months in patients who are at high ischemic risk but not at high bleeding risk. Specific populations, including patients revascularized through coronary artery bypass grafting and patients receiving long-term oral anticoagulant therapy, have gained attention due to the challenges that these conditions pose to the choice of antiplatelet regimen. As the pathophysiology of thrombotic complications after coronary artery bypass grafting differs from that of thrombotic complications post PCI, and there is generally less evidence to support DAPT in these patients, long-term aspirin monotherapy is the current standard, while clopidogrel-based DAPT should be reserved to those patients with a higher risk of graft failure. Patients on chronic oral anticoagulation undergoing PCI, instead, are already at increased risk of bleeding, and antiplatelet agents should be minimized to reduce bleeding events. Specifically, DAPT with aspirin and clopidogrel should be administered only for a short period of time (e.g., 1 week), and then followed by clopidogrel monotherapy up to 1 year on top of oral anticoagulant to achieve the optimal balance between ischemic and bleeding risk. However, after 1 year, patients should stop all antiplatelet agents and maintain oral anticoagulation alone.