Hypoxia-inducible factors (HIFs) are widely expressed in human cancers, with HIF1α and HIF2α previously thought to promote tumor progression through overlapping functions. However, recent data from genome-wide analyses, genetically engineered mouse models, and systems biology approaches have challenged this simple model, revealing unique and sometimes opposing activities of HIFα in normal physiology and disease. These effects are mediated through regulation of unique target genes and interactions with oncoproteins and tumor suppressors, including MYC and p53. As HIF inhibitors are under clinical evaluation for cancer therapy, a deeper understanding of the distinct roles of HIF1α and HIF2α in human neoplasia is necessary. This review summarizes the rapidly evolving understanding of shared and independent activities of HIF1α and HIF2α in tumor growth and progression, and their implications for selective HIF inhibitors as cancer therapeutics.Hypoxia-inducible factors (HIFs) are widely expressed in human cancers, with HIF1α and HIF2α previously thought to promote tumor progression through overlapping functions. However, recent data from genome-wide analyses, genetically engineered mouse models, and systems biology approaches have challenged this simple model, revealing unique and sometimes opposing activities of HIFα in normal physiology and disease. These effects are mediated through regulation of unique target genes and interactions with oncoproteins and tumor suppressors, including MYC and p53. As HIF inhibitors are under clinical evaluation for cancer therapy, a deeper understanding of the distinct roles of HIF1α and HIF2α in human neoplasia is necessary. This review summarizes the rapidly evolving understanding of shared and independent activities of HIF1α and HIF2α in tumor growth and progression, and their implications for selective HIF inhibitors as cancer therapeutics.