We reflect here on the development of a neuroimmunological concept which has been formulated over the past 5 years through studying microglial cell responses in the facial nerve system. A simple axotomy of the adult rat facial nerve which causes regeneration of facial motor neurons and little, if any, cell death can activate microglial cells just as easily as a full-blown degeneration of the entire nucleus induced by toxic ricin. In both instances, the prompt microglial reaction is characterized by a series of structural and phenotypic changes which are in many ways similar to an immune response, e.g., there is cell proliferation and upregulation of MHC antigens. However, since white blood cells do not participate in the retrograde response of facial motor neurons, we have adopted a notion which views microglia as a CNS-wide network of immunocompetent cells whose morphological dissimilarities from leukocytes are a result of their unique adaptation to the CNS architecture. We have continued our in vivo investigations of the phagocytic and immunophenotypic properties of microglial and perivascular cells during the retrograde reaction of facial motor neurons by using intra-neural injections of fluorogold (FG) and ricin followed by lectin and immunostaining for microglia. Two new findings can be added to the microglial neuroimmune network: (1) Microglia take up FG only after motor neuron degeneration, whereas perivascular cells may take up FG under nondegenerating conditions. (2) Immunologically important molecules, such as MHC class II, CD4, and leukocyte common antigens, are expressed by different microglial subpopulations. Thus there is functional and phenotypic heterogeneity among immunocompetent cells of the CNS.