--- - |2- Angiogenesis is a key enabling feature of mammalian embryonic development and tumor progression, which provides oxygen and nutrients that are required for vessel growth and tumor cell growth, respectively. Hypoxia is a driver of this phenomenon and is considered to be one of the most potent initiators of angiogenesis both in vitro and in vivo through stabilization of the transcription factors, hypoxia‐inducible factor‐1 and ‐2 (HIF‐1 and HIF‐2). Although these proteins are highly homologous, emerging evidence suggests that they have unique transcriptional targets and differential impact on angiogenesis. Although HIF‐1α is the best known and widely described isoform, recent studies suggest that HIF‐2α is a critical regulator of physiological and pathophysiological angiogenesis and, at least, the similiarly important as HIF‐1α. Indeed, HIF‐2α has been shown to regulate multiple aspects of angiogenesis, including cell proliferation, migration, maturation of blood vessels, and metastasis. In this review, we focus on recent insights into HIF‐2α expression, activation, and function under hypoxic and nonhypoxic conditions. We also summarize the current knowledge on the crosstalk between HIF‐2 and angiogenesis, describing reported phenotypical changes of HIF‐2α genetic models and HIF‐2 target genes implicated in angiogenesis. Finally, we provide a survey of recent pharmacologic strategies to specifically target HIF‐2 activity. - Journal of Cellular Physiology, Volume 233, Issue 12, Page 9087-9098, December 2018.