Multicellular organisms have developed sophisticated physiologic mechanisms by which they maintain their tissues at the optimal oxygen concentration. This level is important so that the benefits of free oxygen can be realized, while limiting the potential harms. Despite these efforts, there exist physiologic and pathophysiologic conditions where oxygen delivery drops below what is necessary for the tissue. Under these circumstances, the cell then goes through a series of coordinated responses in a time and oxygen concentration-dependent manner. The gene expression changes are designed to maintain cellular and tissue viability, and are comprised of transcriptional as well as post-transcriptional events. As we understand more about the hypoxic response, we realize how it can impact normal development, wound healing, and the malignant progression of a solid tumor.