Hypoxia is a common microenvironmental characteristic of tumor tissue. It drives protumorigenic pathways, primarily via the stabilization and transcriptional activation of hypoxia-inducible factor (HIF). Relatively little is known about the specific role(s) of hypoxia and HIF in bone tumors, either primary bone sarcoma or cancer metastasis to bone. This chapter will describe the methods used to measure the oxygenation level within the normal bone microenvironment, as well as the effects of tumor cell infiltration upon this concentration. Using osteosarcoma as an example, it will describe how hypoxia and HIF drive tumor cell proliferation, protect against apoptosis, promote angiogenesis and epithelial-mesenchymal transition, stimulate osteoclast formation and activity, drive invasion and metastasis, and promote chemo- and radioresistance in primary tumors of bone. The mechanisms by which hypoxia and HIF promote homing of extraskeletal primary tumors to the bone and subsequent metastatic tumor growth within the skeletal site will be discussed, including priming of the premetastatic bone niche, formation of cancer stem cells, regulation of tumor cell dormancy, and establishment of the “vicious cycle.” Finally, different approaches toward therapeutic targeting of hypoxia and HIF-regulated pathways in bone cancer will be discussed.