Microglial cells account for approximately 20% of the total glial population in the central nervous system. They are distributed with no significant local differences in the white and grey matters. In contrast to astrocytes they cover non-overlapping territories. They belong to the mononuclear phagocyte system and form the resident macrophages in the brain tissue, the spinal cord and the retina. Their function in the normal neural parenchyma is unknown. However, in various pathologies they form a most reactive sensor to threats to the nervous system. Within a few hours they exhibit an activation program that we have studied in seven different experimental paradigms, e.g. following nerve section, direct brain trauma, toxic lesion, spreading depression, ischemic lesion, fiber degeneration, autoimmune diseases. Activated microglial cells become immuno-competent and are MHC (major histocompatibility complex) class 1 and class 2 positive. They express the amyloid precursor protein, APP. The complement receptor CR3bi is quickly upregulated. The mitotic activity depends on the colony stimulating factors M-CSF and GM-CSF and the appropriate receptors. Molecules discussed as signals in the activation process of microglia are cytokines such as IL-1, IL-2, IL-6, TGF beta 1. An important role could also be attributed to the unique potassium channel of microglia. Brain macrophages of microglial origin have a strong respiratory burst activity, meaning that they produce oxygen radicals. They also possess Cathepsin B and L and thus are potentially cytotoxic. Taken together, microglia are highly reactive, mobile and multifunctional immune cells of the CNS that can play a universal role in the defence of the neural parenchyma.