Oxygen is an essential element in the survival of complex organisms, however the level of oxygen, low or high, can be a source of stress depending on the biological context. Low levels of oxygen in tissues (hypoxia) can be the consequence of a number of pathophysiological conditions including ischemic disorders and cancer while relative, higher levels (hyperoxia) can lead to retinopathy of prematurity. The local oxygen environment and oxygen consumption dictate vascular homeostasis, vaso-proliferation and vaso-cessation, which is deregulated in these diseases through oxygen-dependent growth factors. In this review, we will introduce aspects of the physiology and biology of oxygen partial pressure and the molecular mechanisms implicated in oxygen sensing. We will outline the regulation and function of the key operator in cellular signalling of hypoxia, the transcription factor, hypoxia-inducible factor. In addition, we will focus on cancer cell hypoxia and on its role in driving cell metabolism, pH regulation and survival.