Primary percutaneous coronary intervention (PCI) is the recommended reperfusion strategy for patients with acute ST-segment elevation myocardial infarction (STEMI). Despite timely-fashion myocardial reperfusion, iterative refinements in drug-eluting stent technology, modern potent antithrombotic therapies and effective secondary prevention measures, the mortality and morbidity rates of patients with STEMI undergoing primary PCI have largely plateaued over the last decade and remain unacceptably high worldwide, disclosing the need for the continuous development of novel therapeutic strategies to further improve clinical outcomes in patients undergoing primary PCI for STEMI. The pathophysiology of acute myocardial infarction is extremely complex. The highly prothrombotic and proinflammatory milieu of acute STEMI results in delayed vascular healing and stent-related adverse events following primary PCI, thus posing major challenges to interventional approaches designed to improve the long-term clinical outcomes of patients with STEMI undergoing primary PCI. Newer-generation drug-eluting stents were introduced to reduce vascular wall injury, mitigate chronic inflammatory responses, and promote rapid endothelialization compared to earlier-generation coronary stent technologies in patients with STEMI. We performed the first head-to-head randomized controlled trial powered for superiority comparing two contemporary newer-generation drug-eluting stents in patients with acute STEMI undergoing primary PCI. The results of our study advocate for the use of newer-generation biodegradable polymer sirolimus-eluting stents as the new gold standard for primary PCI in patients with STEMI. Routine intracoronary aspiration thrombectomy during primary PCI is currently not recommended, but the selective use of manual thrombus aspiration might remain an attractive treatment option for selected STEMI patients. We investigated the influence of temporal patterns on the clinical benefits of aspiration thrombectomy in unselected STEMI patients undergoing primary PCI and found that STEMI patients with short total ischemic times and undergoing primary PCI between 6 am and 6 pm may derive greater clinical benefits from the selective use of manual thrombus aspiration. Finally, early and effective inhibition of the platelet P2Y12 receptor is currently recommended for patients undergoing primary PCI for STEMI. Morphine, an intravenous opioid agent which is routinely administered for pain relief in the setting of acute STEMI, however reduces the absorption and delays the onset of action of orally administered P2Y12 receptor inhibitors in patients with STEMI. We performed the first head-to-head randomized trial comparing the differential effects of morphine and fentanyl, a potent, rapid-acting and effective intravenous synthetic opioid agent, on the pharmacodynamic and pharmacokinetic profiles of ticagrelor, a potent oral P2Y12 receptor inhibitor, in patients with acute STEMI undergoing primary PCI. Our study results support to the use of fentanyl rather than morphine in symptomatic STEMI patients undergoing primary PCI after pre-treatment with a P2Y12 receptor antagonist in contemporary clinical practice.