Hypoxia-inducible transcription factors (HIFs) mediate the cellular response to hypoxia. HIF-DNA binding triggers a transcriptional program that acts to both restore oxygen homeostasis and adapt cells to low oxygen availability. In this context, HIF is centrally involved in many physiologic and pathophysiological processes such as development, high altitude adaptation, ischemic disease, inflammation, and cancer. The recent development of chromatin immunoprecipitation coupled to genome-wide DNA sequence analysis allows the position and extent of HIF binding to DNA to be characterized across the entire genome and correlated with genetic, epigenetic, and transcriptional analyses. This review summarizes recent pan-genomic analyses of HIF binding and HIF-dependent transcriptional regulation.