Primary percutaneous coronary intervention (PCI) has revolutionized the management of ST-elevation myocardial infarction (STEMI), markedly improving patient outcomes. Despite technological advancements, pharmacological innovations, and refined interventional techniques, STEMI prognosis remains burdened by a persistent incidence of cardiac death and heart failure (HF), with mortality rates plateauing over the last decade. This review examines current practices in primary PCI, focusing on critical factors influencing patient outcomes. Moreover, it explores future developments, emphasizing the role of microvascular dysfunction—a critical but often under-recognized contributor to adverse outcomes, including incident HF and mortality, and has emerged as a key therapeutic frontier. Strategies aimed at preserving microvascular function, mitigating ischemia–reperfusion injury, and reducing infarct size are discussed as potential avenues for improving STEMI management. By addressing these challenges, the field can advance toward more personalized and effective interventions, potentially breaking the current deadlock in mortality rates and improving longer-term prognosis.