All cells with a nucleus "sense" the concentration of O2 and respond to hypoxia. The major mediator of oxygen homeostasis in mammalian cells is a transcription factor called hypoxia-inducable factor 1 (HIF-1). HIF is a heterodimeric complex consisting of two protein subunits, HIF-α and HIF-β. The α subunit has isoforms 1α, 2α and 3α and all three heterodimerize with 1β. In the presence of oxygen (under normoxic conditions), the HIF complex is inactivated by posttranslational hydroxylation of the α subunit by the enzyme prolyl-4-hydroxylase (HIF-PH or PHD - prolyl hydroxylase domain), followed by degradation of the HIF-1α subunit regulated by von Hippel-Lindau tumor suppressor protein (pVHL). Lack of oxygen and lack of hydroxylation of the HIF-α subunit, due to which it would degrade in normoxia, its stabilization and translocation in the nucleus and consequent activation of the HIF-complex, changes in oxygen availability are converted into changes in gene expression, transcriptional response to hypoxia. HIFs directly or indirectly regulate the expression of several hundred genes in all cell types and trigger cascading secondary responses by intertwining with multiple signaling pathways. The HIF-α protein thus regulates many responses to hypoxia including adaptations to anaerobic metabolism, enhances the intensity of erythropoiesis, angiogenesis, affects vasomotor functions, and respiration. Physiological mechanisms that are activated in hypoxia tend to supply insufficiently oxygenated tissue with oxygen. The HIF complex is essential for normal development and plays a role in the pathophysiological responses to ischemia/hypoxia. Overexpressed HIF-1/2α protein is associated with tumor progression and metastatic potential, resistance to radiotherapy and chemotherapy, and higher patient mortality, and vascular endothelial growth factor (VEGF) affects the angiogenesis of somatic and tumor cells. In preclinical and clinical studies, inhibition of HIF-1/2α activity has effects on tumor angiogenesis and growth, and work is continuously ongoing to develop selective HIF-1/2α inhibitors. This paper summarized the findings on how cells "sense" and respond to oxygen availability, how this is associated with malignant tumors, and how these findings can be used in therapy.