Percutaneous coronary intervention (PCI) improves symptoms and prognosis in ischemia-inducing, functionally significant, coronary lesions. Use of fractional flow reserve allows physicians to investigate the ischemia-inducing potential of a specific lesion and can be used to guide coronary revascularization, especially in multivessel coronary artery disease. Fractional flow reserve-guided PCI has been extensively investigated. Results show that deferral of stenting in non-significant lesions is safe, whereas deferral of stenting in functionally significant lesions worsens outcome. FFR-guided PCI improves outcome in multivessel disease over angiography-guided PCI. Until recently, there was little known about the long-term outcome of FFR-guided revascularization and its validity in acute coronary syndromes. This review aims to address the new evidence regarding long-term appropriateness of FFR-guided PCI, the need for hyperemia to evaluate functional severity, and the use of FFR in acute coronary syndromes.