Simple SummaryHypoxia, or low oxygen levels within tumor tissue, presents a significant challenge for the management of hepatocellular carcinoma (HCC). Hypoxic microenvironments can induce changes in gene expression and cellular metabolism that promote tumor growth, metastasis, and resistance to chemotherapy and radiation therapy, making the cancer cells more aggressive and difficult to treat. Targeting hypoxia in HCC has emerged as a promising strategy for improving treatment outcomes. The aim of this review is to summarize the current knowledge on the role and biochemical pathways of hypoxia in the progression of HCC. This review also discusses the potential therapeutic options for targeting hypoxia for the management of HCC.AbstractHypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as well as a hypoxic tumor, due to the liver being a relatively hypoxic environment compared to other organs. Trans-arterial chemoembolization (TACE) and trans-arterial embolization (TAE) are locoregional therapies that are part of the treatment guidelines for HCC but can also exacerbate hypoxia in tumors, as seen with HIF-1α upregulation post-hepatic embolization. Hypoxia-activated prodrugs (HAPs) are a novel class of anticancer agent that are selectively activated under hypoxic conditions, potentially allowing for the targeted treatment of hypoxic HCC. Early studies targeting hypoxia show promising results; however, further research is needed to understand the effects of HAPs in combination with embolization in the treatment of HCC. This review aims to summarize current knowledge on the role of hypoxia and HIF-1α in HCC, as well as the potential of HAPs and liver-directed embolization.