Background We aimed to determine the change in treatment strategies and times to treatment over the first 5 years of the Mission: Lifeline program. Methods and Results We assessed pre- and in-hospital care and outcomes from 2008 to 2012 for patients with ST -segment-elevation myocardial infarction at US hospitals, using data from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines Registry. In-hospital adjusted mortality was calculated including and excluding cardiac arrest as a reason for primary percutaneous coronary intervention delay. A total of 147 466 patients from 485 hospitals were analyzed. There was a decrease in the proportion of eligible patients not treated with reperfusion (6.2% versus 3.3%) and treated with fibrinolytic therapy (13.4% versus 7.0%). Median time from symptom onset to first medical contact was unchanged (≈50 minutes). Use of prehospital ECGs increased (45% versus 71%). All major reperfusion times improved: median first medical contact-to-device for emergency medical systems transport to percutaneous coronary intervention-capable hospitals (93 to 84 minutes), first door-to-device for transfers for primary percutaneous coronary intervention (130 to 112 minutes), and door-in-door-out at non-percutaneous coronary intervention-capable hospitals (76 to 62 minutes) (all P<0.001 over 5 years). Rates of cardiogenic shock and cardiac arrest, and overall in-hospital mortality increased (5.7% to 6.3%). Adjusted mortality excluding patients with known cardiac arrest decreased by 14% at 3 years and 25% at 5 years ( P<0.001). Conclusions Quality of care for patients with ST -segment-elevation myocardial infarction improved over time in Mission: Lifeline, including increased use of reperfusion therapy and faster times-to-treatment. In-hospital mortality improved for patients without cardiac arrest but did not appear to improve overall as the number of these high-risk patients increased.