The concept of using fractional flow reserve (FFR) to predict the functional significance of coronary lesions was described > 20 years ago. In 1996, Pijls et al showed that measurements of FFR in the cardiac catheterization laboratory can accurately predict provoked ischemia upon non-invasive functional testing. The DEFER study (2007) showed that coronary lesions with non-ischemic FFR values can be treated with medical therapy with good clinical outcome at 5-year follow up. The FAME-1 study (2009) evaluated the strategy of PCI guided by angiography versus PCI guided by FFR measurements in multi-vessel disease. The primary end-point was the 1-year composite of death, myocardial infarction (MI), and any repeat revascularization. Fewer stents were used per patient for the FFR-guided group (2.7 versus 1.9 stents per patient), less contrast agent used (302 versus 272 ml), and lower in-lab equipment cost ($6,007 US versus $5,332 US), all significant with P<0.001. A total of 1,005 patients were randomized. At 1-year follow up, the composite end-point of death, MI and target vessel revascularization was 18.2% for the angiography-guided group versus 13.3% for the FFR-guided group (p < 0.02). At 2-year follow up, the incidence of death and MI was lower for the FFR-guided group (12.7% versus 8.4%, p<0.03), and the incidence of MI in the FFR-guided and PCI deferred population was very low at 0.2%.