Cells and molecules of the immune system contribute to brain pathology as well as to brain homeostasis. We suggest that there are numerous anti-brain antibodies that can cause acute neuronal dysfunction if they penetrate brain parenchyma. Many of these acute immune-mediated insults may alter the homeostatic mechanisms in the brain and initiate pathologic events that no longer depend on the presence of the inciting antibody, but rather on microglial cell activation. This paradigm, if correct, suggests that there may be two potential moments of therapeutic intervention. The first moment is when antibody contacts cells of the central nervous system and the second is when microglia become activated and impair normal neuronal functions. In this review, we discuss data that support this model for immune-mediated pathology in both the adult brain and the developing fetal brain.