Microglia and astrocytes in the central nervous system are now recognized as active participants in various pathological conditions such as trauma, stroke, or chronic neurodegenerative disorders. Their activation is closely related with the development and severity of diseases. Interestingly, activation of microglia and astrocytes occurs with a spatially and temporarily distinct pattern. The present review explores the cross talk in the process of their activation. Microglia, activated earlier than astrocytes, promote astrocytic activation. On the other hand, activated astrocytes not only facilitate activation of distant microglia, but also inhibit microglial activities. Molecules contributing to their intercommunication include interleukin-1 (IL-1), adenosine triphosphate (ATP), and transforming growth factor beta (TGF-β). A better understanding about the cross talk between activation of microglia and astrocytes would be helpful to elucidate the role of glial cells in pathological conditions, which could accelerate the development of treatment for various diseases.