Rapid and consistent platelet inhibition represents the cornerstone of pharmacologic treatment in the early hours of ST-segment elevation myocardial infarction (STEMI). Oral P2Y₁₂ inhibitors are recommended to be administered as early as possible in patients with STEMI undergoing primary percutaneous coronary intervention. However, a delay in the onset of antiplatelet agent effects has been recently described in the first several hours after oral administration of clopidogrel, prasugrel, and ticagrelor. As a result, primary percutaneous coronary intervention is performed in most cases with P2Y₁₂ inhibition that may be inadequate. Several strategies may be applied in order to “bridge the gap” in platelet inhibition after oral P2Y₁₂ inhibitors in STEMI, such as upstream administration of P2Y₁₂ inhibitors, loading dose modification, use of an intravenous P2Y₁₂ inhibitor, or glycoprotein IIb/IIIa inhibitors' administration. These strategies may further improve clinical outcomes in this high-risk “golden window.”