All aerobic organisms require molecular oxygen to generate metabolic energy for normal growth and survival. During evolution, multi-cellular organisms have developed and refined complex networks for adaptation to hypoxic environments at both systemic and cellular levels. Adaptation to hypoxia largely results from changes in the activity and expression of key proteins. These include proteins involved in increasing oxygen delivery to hypoxic tissues and proteins that facilitate glycolysis for anaerobic metabolism. The mammalian transcription factor hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. More than 100 target genes of HIF mediate broad systemic and local responses to hypoxia, including angiogenesis/vascular remodeling, erythropoiesis, glucose transport, glycolytic metabolism, and cell proliferation. Many human diseases such as myocardial ischemia, stroke, cancer, and chronic lung disease cause hypoxic stress, and HIF is a critical mediator for pathophysiological responses to hypoxia. Elucidating cellular and molecular mechanisms underlying regulation of HIF activity may enable novel therapeutic approaches. The C. elegans hif-1 gene is orthologous to mammalian HIF-alpha gene, and C. elegans has proven to be a powerful system for the study of hypoxia-inducible factor regulation and function. In this dissertation, I studied the role of HIF-1 in hypoxia response and initiated genetic studies to identify HIF-1 regulators in C. elegans. I demonstrate that C. elegans hif-1 regulates the majority of early transcriptional responses to hypoxia. My studies also provide clear evidence for HIF-1-independent pathways for adaptation to oxygen deprivation. Finally, I discovered a novel membrane-bound protein that regulates the activity of C. elegans HIF-1 in a potential negative feedback loop.