Angiogenesis plays an important role in tumor growth and metastasis. Targeting tumor vascular endothelial cells to inhibit tumor angiogenesis and thus block tumor blood and nutrition supply is the current research focus on anti-tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) signal pathway regulates the proliferation, migration, survival and angiogenesis of vascular endothelial cells, which is abnormally activated in different tumors. Studies have confirmed that inhibiting VEGF/VEGFR-2 signaling pathway can produce anti-tumor effect. Nowadays, anti-angiogenesis therapy targeting VEGF/VEGFR-2 inhibition has become the most effective clinical strategy for cancer treatment. Therefore, a variety of VEGF/VEGFR-2 inhibitors with different structures have been developed. A few selectively inhibit VEGF to block the activation of VEGFR-2 pathway, while the majority selectively inhibit VEGFR-2 as multi-target inhibitors. Based on the classification of dominant skeletons, this paper briefly analyzes the biological activity, clinical research process and structure-activity relationship of the representative small molecule inhibitors of VEGF/VEGFR-2.