The selection and optimal duration of pharmacological agents to counteract thrombotic processes activated in patients with ST-elevation myocardial infarction (STEMI) still remain a debated issue in current clinical practice. Recently published trials have highlighted the potential benefits of dual-antiplatelet therapy (DAPT) extended beyond the currently recommended 12-months term. Anticoagulation with non-vitamin K oral anticoagulants in addition to DAPT has also been explored. Importantly, benefits of prolonged antithrombotic management strategies could be offset by harms following bleeding complications, therefore careful assessment of a patient benefit-risk profile must be used to drive individualized medical decisions. Appraising current available evidence is useful to inform clinical practice and to optimize the pharmacological management of patients with STEMI. Accordingly, we provide an overview of the literature focusing on long-term antithrombotic management strategies in patients with a recent or prior myocardial infarction, with a primary focus on STEMI.