Abstract Hypoxia has wide-ranging impact in normal physiology and disease processes. This stimulus evokes changes in gene expression mediated by transcription factors termed hypoxia-inducible factors (HIFs) that affect numerous processes: angiogenesis, cell survival, cellular metabolism, stem cell self-renewal and multipotency, migration, invasiveness, and metastatic progression in tumor cells. Over the past decade, increasing numbers of reports have emerged documenting differential roles of HIF1α and HIF2α in these processes. In cells of the sympathoadrenal lineage, both HIFs differentially mediate influences of hypoxia on catecholamine synthesis and secretion, but HIF2α signaling has particularly prominent functions in regulating developmental processes of growth and differentiation. This chapter discusses the role of HIF2α and HIF1α in the context of the development, phenotypic features, and functions of chromaffin cells. Moreover, current knowledge about tumor formation in cells of the sympathoadrenal lineage, leading to catecholamine-producing pheochromocytomas and paragangliomas, is analyzed in the light of the HIF2α signaling network.