Astrocytes are increasingly being recognized as dynamic participants in many aspects of normal central nervous system function. In disease states, reactive astrocytes undergo complex phenotypic changes, generically referred to as astrogliosis. Unraveling the functions of reactive astrocytes and underlying molecular mechanisms is a difficult problem. The use of genetically modified mice is beginning to yield some answers to long-standing questions in the field. What are the functions of reactive astrocytes? What extracellular factors and intracellular signaling mechanisms are responsible for astrocyte activation in various forms of neural injury? In this review we will highlight studies using astrocyte reporter lines for cellular imaging and lineage tracing, as well as gain- and loss-of-function mutations that have begun to shed light on mechanisms of astrogliosis.