The P2Y12 receptor plays a pivotal role in platelet activation and aggregation through a complex cascade of actions. Laboratory and clinical data have convincingly shown the benefit of P2Y12 inhibition combined with aspirin in patients with acute coronary syndrome (ACS)/undergoing percutaneous coronary intervention (PCI). Newer agents - like prasugrel, ticagrelor, and cangrelor - provide more consistent, faster, and stronger platelet inhibition than clopidogrel. In large clinical trials newer agents have resulted in fewer ischemic complications (though with increased bleeding potential) than clopidogrel. High-risk subpopulations like ST-segment elevation myocardial infarction, diabetes, chronic kidney disease, elderly, and low body weight patients have been identified. A 'return to the laboratory' has been observed recently, with several pharmacodynamic studies being performed particularly in these cohorts. This interplay between research laboratory and clinical data may lead to a more efficient and safer use of P2Y12 inhibitors.