The tumor microenvironment (TME) is an intricate environment consisting of distinct cell types, aberrant vasculature, and immunosuppressive cytokines promoting tumor growth and progression. Tumor development is characterized by abnormal growth, which results in increased oxygen metabolism and, as a result, hypoxia (reduced oxygen availability). The presence of intra-tumoral hypoxia is a common characteristic in solid tumors, and it is associated with the augmented activity of hypoxia-inducible factors (HIFs), which influence the expression of genes that are involved in metabolic reprogramming, epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, angiogenesis, migration, invasion, metastasis, cancer stem cell (CSC) maintenance, immune escape, and resistance to chemotherapy and radiation therapy, presenting a major hurdle in cancer therapy. This chapter will present comprehensive knowledge about the role of hypoxia in TME, hypoxia-related signaling pathways, and the impacts of hypoxia on the function of immune cells and immune escape. Additionally, strategies for targeting hypoxia-induced pathways will be discussed.