Maintaining a sufficient oxygen supply to cells and tissues is essential for the survival and proper functioning of aerobic organisms. The condition known as hypoxia arises when the demand for oxygen exceeds its supply, potentially leading to the loss of biological functions and even death. Higher multicellular organisms have evolved specialized mechanisms within their respiratory and cardiovascular systems to ensure that all cells receive an adequate oxygen supply. These mechanisms include the lungs, hemoglobin in red blood cells, the diaphragm, respiratory support muscles, and neuroepithelial cells responsible for sensing the partial pressure of oxygen. The proper development and maintenance of these intricate systems necessitate the coordinated expression of thousands of genes. Central to this gene expression regulation is the role of Hypoxia-inducible factors (HIFs), which serve as transcription factors. The regulation of HIFs seems to hinge significantly on cells utilizing oxygen deprivation as a signal to control HIFs’ stability and transcriptional activity. HIFs, as transcription factors, activate the transcription of genes crucial for adapting to hypoxic (low oxygen level) environments. This chapter delves into the intricate regulatory mechanisms governing HIFs and explores their potential application as a promising approach in cancer treatment. The discussion encompasses the distinctive properties of HIFs, the challenges associated with their delivery, and the strategies employed to overcome these obstacles. Furthermore, this chapter highlights the promising outcomes achieved thus far and outlines potential future directions in this evolving field.