Oligodendrocytes (OLG) have more complex interactions with nitric oxide (NO) than initially suspected. Historically, OLG were seen only as targets of high NO levels released from other cells. Expression of nitric oxide synthase type II (NOS-2) in primary cultures of OLGs stimulated by cytokines led to controversy due to the presence of small numbers of microglia, cells also inducible for NOS-2 expression. The present review summarizes the findings that immature OLG express NOS-2, but that they do not in their most mature stage in culture as membrane sheet-bearing cells. This raises questions about the regulation of NOS-2 expression in OLG. Additionally, novel data are presented on NOS-3 expression in cultured OLG. If confirmed in vivo, this finding suggests that constitutive NOS-3 expression may play a key role in OLG injury due to its activation by calcium, in interaction with pathways mediating glutamate toxicity. The authors discuss in vivo NO levels to place in vitro findings in context, and compare OLG sensitivity to NO with that of other brain cells. Lastly, the multiple interactions of NO are considered with regard to glutamate cytotoxicity, the antioxidant glutathione, mitochondrial function, and myelin architecture.