The HIF-2?-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization -- Hypoxia and Hypoxia Inducible Factors in Cancer Stem Cell Maintenance -- Role of Carcinoma-Associated Fibroblasts and Hypoxia in Tumor Progression -- The Role of Hypoxia Regulated microRNAs in Cancer -- Oxygen Sensing: A Common Crossroad in Cancer and Neurodegeneration -- Hypoxia-Inducible Factors as Essential Regulators of Inflammation -- Hypoxia and Metastasis in Breast Cancer. Solid tumors frequently contain areas of oxygen deprivation (hypoxia) due to rapid cell proliferation and/or vascular insufficiency. The presence of hypoxic domains typically correlates with poor patient prognosis, due to the relative resistance of hypoxic cells to conventional cancer therapies and effects of O2 availability on disease progression. The response of malignant cells to hypoxia has been the focus of intense research over the last decade. In this issue of Current Topics in Microbiology and Immunology, the authors present articles describing the impact of hypoxia on components of the tumor microenvironment (such as endothelial cells, inflammatory cells, and tumor associated fibroblasts), the expression of unique microRNAs, tumor cell differentiation status, and metastasis. Each review article describes the state of the field studying these topics, and poses important questions for the future. The overall goal is to depict tumor phenotypes and associated molecular pathways to be exploited in the development of novel therapeutics to be used against a broad spectrum of human cancers.