Purinergic signaling in the nervous system has been the focus of a considerable number of studies since the 1970s. The P2X and P2Y receptors are involved in the initiation of purinergic signaling. They are very abundant in the central and peripheral nervous systems, where they are expressed on the surface of neurons and glial cells--microglia, astrocytes, oligodendrocytes and Schwann cells and the precursors of the latter two. Their ligands--extracellular nucleotides--are released in the physiological state by astrocytes and neurons forming synaptic connections, and are essential for the proper functioning of nervous system cells. Purinergic signaling plays a crucial role in neuromodulation, neurotransmission, myelination in the CNS and PNS, intercellular communication, the regulation of ramified microglia activity, the induction of the response to damaging agents, the modulation of synaptic activity and other glial cells by astrocytes, and the induction of astrogliosis. Understanding these mechanisms and the fact that P2 receptors and their ligands are involved in the pathogenesis of diseases of the nervous system may help in the design of drugs with different and more effective mechanisms of action.