Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide. The predominant type of primary liver cancer is hepatocellular carcinoma (HCC). Tumor vascular endothelial cells (VECs), a major component of cells in the microenvironment of HCC, play multifaceted roles in contributing to tumor angiogenesis, proliferation, and migration, as well as therapeutic resistance by attracting myeloid-derived suppressor cells and suppressing cytotoxic CD8 T cell differentiation and function. Recently, Wu reported that apatinib, an inhibitor of vascular endothelial growth factor receptor 2, can inhibit tumor VEC glycolysis by regulating phosphatidylinositol 3-kinase/protein kinase B/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 signaling pathway to suppress HCC progression. With great interest, this editorial paper aims to review the function and key molecular signaling pathways of tumor VECs in HCC initiation and progression and summarize potential treatment options in clinical trials.