Our view of the immune privileged status of the brain has dramatically changed during the past two decades. Even though systemic immune stimuli have the ability to activate different populations of neurons, cells of monocytic lineage also have access to the neuronal tissue and populate it as microglia. Although such a phenomenon is limited in intact brains, it is greatly increased during neurodegenerative processes associated with innate immunity and the release of pro-inflammatory molecules by either resident microglia or those derived from the bone marrow stem cells. The role of these events is currently a matter of great debate and controversy, especially as it relates to brain protection, repair, or further injury. In recent years, accumulating data have supported the notion that when immune molecules are timely released by microglia, they limit neuronal injury in the presence of pathogens and toxic agents, help clear debris from degenerated cells, and restore the cerebral environment for repair. It has been shown that alteration of the natural innate immune response by microglia has direct consequences in exacerbating the damages following acute injury to neurons. This article presents and discusses these data, supporting a powerful neuroprotective role for microglia and their innate immune reactions in response to pathogens and central nervous system insults.