Reactive astrocytes are associated with a vast array of central nervous system (CNS) pathologies. The activation of astrocytes is characterized by changes in their molecular and morphological features, and depending on the type of damage can also be accompanied by inflammatory responses, neuronal damage, and in severe cases, scar formation. Although reactive astrogliosis is the normal physiological response essential for containing damage, it can also have detrimental effects on neuronal survival and axon regeneration, particularly in neurodegenerative diseases. It is believed that progressive changes in astrocytes as they become reactive are finely regulated by complex intercellular and intracellular signaling mechanisms. However, these have yet to be sorted out. Much has been learned from gain-of-function approaches in vivo and culture paradigms, but in most cases, loss-of-function genetic studies, which are a critical complementary approach, have been lacking. Understanding which signaling pathways are required to control different aspects of astrogliosis will be necessary for designing therapeutic strategies to improve their beneficial effects and limit their detrimental ones in CNS pathologies. In this article, we review recent advances in the mechanisms underlying the regulation of aspects of astrogliosis, with the main focus on the signaling pathways that have been studied using loss-of-function genetic mouse models.