The function of oligodendrocytes is to myelinate CNS axons. Oligodendrocytes and the axons they myelinate are functional units, and neurotransmitters released by axons can influence all stages of oligodendrocyte development via calcium dependent mechanisms. Some of the clearest functional evidence is for adenosine, ATP, and glutamate, which are released by electrically active axons and regulate the migration and proliferation of oligodendrocyte progenitor cells and their differentiation into myelinating oligodendrocytes. Glutamate and ATP, released by both axons and astrocytes, continue to mediate Ca2+ signaling in mature oligodendrocytes, acting via AMPA and NMDA glutamate receptors, and heterogeneous P2X and P2Y purinoceptors. Physiological signalling between axons, astrocytes, and oligodendrocytes is likely to play an important role in myelin maintenance throughout life. Significantly, ATP- and glutamate-mediated Ca2+ signaling are also major components of oligodendrocyte and myelin damage in numerous pathologies, most notably ischemia, injury, periventricular leukomalacia, and multiple sclerosis. In addition, NG2-expressing glia (synantocytes) in the adult CNS are highly reactive cells that respond rapidly to any CNS insult by a characteristic gliosis, and are able to regenerate oligodendrocytes and possibly neurons. Glutamate and ATP released by neurons and astrocytes evoke Ca2+ signaling in NG2-glia (synantocytes), and it is proposed these regulate their differentiation capacity and response to injury. In summary, clear roles have been demonstrated for neurotransmitter-mediated Ca2+ signaling in oligodendrocyte development and pathology. A key issue for future studies is to determine the physiological roles of neurotransmitters in mature oligodendrocytes and NG2-glia (synantocytes).