Oxygen is a substrate in the synthesis of the neurotransmitters, norepinephrine, dopamine, and serotonin. Changes in environmental oxygen appear to cause corresponding alterations in brain monoamine synthesis in vivo. The effect of chronic hypoxia was studied by exposing rats to 10% oxygen for up to 36 h. Brain monoamine synthesis, estimated in vivo, decreased initially and then returned to control levels, despite continued exposure to 10% oxygen. During this apparent adaptation to hypoxia, there were no changes in the concentration of brain serotonin, norepinephrine, dopamine, or tryptophan, while brain tryosine increased after 24 h of exposure. Tyrosine hydroxylase activity in vitro was not altered by the exposure to 10% oxygen. Evidence of hypoxic adaptation in these rats, a rightward shift of their hemoglobin dissociation curves, was found after 24 h of exposure. The adaptation of brain monoamine synthesis to hypoxia appeared to correlate with adaptive changes in brain tissue oxygen rather than any change in the intraneuronal regulation of amine synthesis.