The activation of microglia has been recognized for over a century by their morphological changes. Long slender microglia acquire a short sturdy ramified shape when activated. During the past 20 years, microglia have been accepted as an essential cellular component for understanding the pathogenic mechanism of many brain diseases, including neurodegenerative diseases. More recently, functional studies and imaging in mouse models indicate that microglia are active in the healthy central nervous system. It has become evident that microglia release several signal molecules that play key roles in the crosstalk among brain cells, i.e., astrocytes and oligodendrocytes with neurons, as well as with regulatory immune cells. Recent studies also reveal the heterogeneous nature of microglia diverse functions depending on development, previous exposure to stimulation events, brain region of residence, or pathological state. Subjects to approach by future research are still the unresolved questions regarding the conditions and mechanisms that render microglia protective, capable of preventing or reducing damage, or deleterious, capable of inducing or facilitating the progression of neuropathological diseases. This novel knowledge will certainly change our view on microglia as therapeutic target, shifting our goal from their general silencing to the generation of treatments able to change their activation pattern.