Microglia are the resident immunocompetent cells of the brain, comparable to other tissue macrophages, eg Kupffer cells in the liver or Langerhans cells in the skin. In disease, however, the central nervous system appears to be a largely immunosuppressive environment, which previously led to the hypothesis that it is an" immunologically privileged" organ. Nevertheless, microglia can be activated by various internal and external stimuli, resulting in expression of cytokines and other mediators of inflammation. The molecular mechanisms converting those signals into specific microglial responses are a field of intensive research efforts. These have been performed both on cultured microglia and in vivo. Although the situation in vivo is sometimes difficult to interpret, considerable progress on the molecular level has been made using a number of excellent animal model systems combined with advanced detection techniques. Moreover, isolation and culture of microglia is becoming a standard method in an increasing number of laboratories, which allows a closer look at their reactions towards a variety of test substances. Both aspects have been covered in this paper. It turns out that microglia are extremely sensitive towards any kind of stimulus. They are probably the first cells in the brain" sensing" changes in the periphery, and the summarized data suggest that microglia may even react in a specific manner in response to a specific stimulus. Under the notion that not only multiple sclerosis, but also further chronic degenerative diseases of the brain, are based on a common autoimmune mechanism, better insights into microglial activation and its prolonged maintenance are of outstanding scientific interest.