Fractional flow reserve (FFR) is a well-validated tool for determining the functional significance of a coronary artery stenosis, facilitating clinical decisions regarding the need for revascularization. FFR-guided revascularization improves clinical and economic outcomes. However, its application remains challenging in certain complex anatomic subsets, including left main coronary artery stenosis, bifurcation disease, and saphenous vein graft disease. This article reviews recent data supporting the use of FFR in these complex anatomic subsets.