Periaqueductal gray(PAG) plays an important role in pain modulation. It is not only an important participant of ascending pain transmission pathways, but also a critical part of descending pain modulation pathways. In PAG, there are evidences that several neurotransmitters (such as γ-aminobutyric acid, 5-hydroxytryptamine, glutamate) and neuromodulators (such as endogenous opioid peptide, cannabinoid) are involved in the information transmission and functional regulation of pain. PAG not only regulates pain locally through their own level changes and interaction of these factors, but also regulates pain by receiving fiber projections from other brain regions and sending fiber projections to other pain related brain regions. For example, the analgesic effect of the increased level of GABA in PAG could be realized by the effect of opioid peptides on GABAergic interneurons, or driven directly by the fiber projection from cortex to the GABAergic interneurons in PAG. GABAergic neurons in PAG can also regulate pain by affecting the NAergic fibers projected from A7 cells to the spinal cord. Thus, PAG participates pain modulation in complicated and multiple ways.