Hepatocellular carcinoma (HCC) is characterized by hypervascularity, indicating that angiogenesis plays a vital role in HCC growth and progression. A number of anti-angiogenic therapies are being utilized in clinical trials in patients with HCC. However, the therapeutic efficacy of anti-angiogenic monotherapy is still insufficient. While inhibition of angiogenesis results in tumor hypoxia and cell death, this inhibition may also activate hypoxia-induced cell signals that may promote HCC progression. Therefore, an understanding of these signals may be essential in designing efficient anti-angiogenic therapies. This review summarizes the role of hypoxia-induced signals in HCC.