The purinergic receptor family contains some of the most abundant receptors in living organisms. A growing body of evidence indicates that extracellular nucleotides play important roles in the regulation of neuronal and glial functions in the nervous system through purinergic receptors. Nucleotides are released from or leaked through nonexcitable cells and neurons during normal physiological and pathophysiological conditions. Ionotropic P2X and metabotropic P2Y purinergic receptors are expressed in the central nervous system (CNS), participate in the synaptic processes, and mediate intercellular communications between neuron and gila and between glia and other glia. Glial cells in the CNS are classified into astrocytes, oligodendrocytes, and microglia. Astrocytes express many types of purinergic receptors, which are integral to their activation. Astrocytes release adenosine triphosphate (ATP) as a "gliotransmitter" that allows communication with neurons, the vascular walls of capillaries, oligodendrocytes, and microglia. Oligodendrocytes are myelin-forming cells that construct insulating layers of myelin sheets around axons, and using purinergic receptor signaling for their development and for myelination. Microglia also express many types of purinergic receptors and are known to function as immunocompetent cells in the CNS. ATP and other nucleotides work as "warning molecules" especially by activating microglia in pathophysiological conditions. Studies on purinergic signaling could facilitate the development of novel therapeutic strategies for disorder of the CNS.