Tumor hypoxia is a feature common to almost all solid tumors due to malformed vasculature and inadequate perfusion. Tumor cells have evolved mechanisms that allow them to respond and adapt to a hypoxic microenvironment. The hypoxia-inducible transcription factor (HIF) family is comprised of oxygen-sensitive alpha (α) subunits that respond rapidly to decreased oxygen levels and oxygen-insensitive beta (β) subunits. HIF binds to specific recognition sequences in the genome and increases the transcription of genes involved in a variety of metabolic and enzymatic pathways that are necessary for cells to respond to an oxygen-poor environment. The critical role of this family of transcriptional regulators in maintaining oxygen homeostasis is supported by multiple regulatory mechanisms that allow the cell to control the levels of HIF as well as its transcriptional activity. This review will focus on how the transcriptional activity of HIF is studied and how it can be exploited for cancer therapy.