Antithrombotic therapy has become increasingly challenging due to the thrombotic and bleeding risk of patients presenting with acute coronary syndrome (ACS) today. Contributing factors include increasing age, underlying comorbidities (e.g., renal failure, atrial fibrillation [AF]), or concomitant interventions including transcatheter valve procedures requiring individualized antithrombotic strategies. Thanks to the development of novel stent platforms with biocompatible polymers and thin strut design allowing for a more rapid endothelialization, shortening or de-escalation of antiplatelet therapies is an attractive option for reducing bleeding events. In fact, several trials have been recently published or are currently underway that address the issue of early monotherapy after short-term dual antiplatelet therapy in ACS patients. Patients with AF and ACS are at a particularly high risk for thromboembolic and bleeding events. An individualized combination approach of antiplatelet therapy plus non-vitamin K oral anticoagulants should be favored in these patients to reduce bleeding risk according to recent randomized trials and guidelines. In contrast to de-escalation strategies in ACS patients at high bleeding risk, in patients with myocardial infarction in whom the long-term risk for ischemic events prevails, prolongation of an intensified antithrombotic therapy on top of acetylsalicylic acid is recommended. This review summarizes the recent evidence and offers practical recommendations to determine patients’ bleeding versus thrombo-ischemic risk in order to tailor early and late antithrombotic therapy after ACS.