Neural systems exposed to diminished oxygen availability have a compromised metabolism that leads to pathophysiological changes or neuronal death, depending on the severity and duration of oxygen deprivation. A distributed network of oxygen sensors responds to protect cells by slowing or ameliorating pathophysiological changes and forestalling neuronal death via short-term or long-term changes involving gene expression and the modification of sensors and effectors. In mammalian systems such protective changes are not sufficient to prevent damage under extreme conditions, unlike some hypoxia and anoxia-tolerant vertebrates which demonstrate oxygen-dependent, reversible reprogramming to protect vital organs such as the brain and heart. This chapter examines (1) the nature of the signal for oxygen sensors; (2) the molecules used to sense oxygen; (3) how the primary signal is generated, converted, and used in an oxygen-dependent manner; (4) how effector systems function in different cell types; and (5) how oxygen sensing pathways are interconnected to more general protective stress responses which confer cross protection for a number of physiological stressors. While future therapies may focus on the activation of hypoxia inducible factor (HIF) and its downstream gene products, selected gene products could be administered to reduce neuronal loss and improve recovery after acute insults due to ischemic events and degenerative diseases of the brain and retina. Activation of neuroprotective pathways by oxygen sensors and other physiological stressors could be used as pre-treatment to minimize neurotrauma associated with neurosurgical procedures and as an ancillary treatment during early stages of rehabilitation.