Microglia--the macrophage equivalent of the CNS--safeguards and supports neuronal functions. Threats to the CNS homeostasis can trigger a rapid transformation of these cells from a normally "resting" into alerted and "activated" states. Microglia primarily serves the tissue defence and protection when participating in mechanisms of innate and adaptive immunity. On the contrary, excessive acute or chronic microglial activation can provoke severe neuronal and glial damage by carrying or fuelling destructive cascades. Several factors and conditions have already been identified that maintain the resting phenotype or organize and control the activation process. Cells are thereby able to recognize a dangerous signal as well as to sense functional disturbance. Microglial activation is also proving a much more variable and adaptive process than previously noticed. Aiming at microglia as a therapeutic target, research may focus on intracellular pathways that are probably common to activation scenarios as triggered by various receptor systems. Certain signalling elements may have key roles in the cytosolic integration of sensory inputs and a conversion into programs of executive performance. As the integrative aspect of microglial activation becomes illuminated hope builds up also on strategies for selective interference with harmful outcomes in favour of the--phylogenetically approved--beneficial potential of these fascinating cells.