Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Reactive astrocytes can have both loss of normal functions and gain of abnormal effects that could feature prominently in a variety of disease processes. This article reviews developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis and highlights the potential to identify novel therapeutic molecular targets for diverse neurological disorders.