Reactive astrocytes have traditionally been viewed as a significant contributor to secondary neuronal damage and repair inhibition after central nervous system (CNS) injury attributed, in large part, to their roles in glial scarring. However, more recent transcriptional evidence has uncovered the vast diversity in reactive astrocyte identity and functions that comprises both neuroprotective and -toxic characteristics. Additionally, the capacity of reactive astrocytes to shift between these activation states demonstrates a high level of environment-dependent plasticity that drives the interplay between neuroprotection and -toxicity after CNS injury. These recent findings have spawned a new field of research that seeks to identify and categorize the function of these discrete subpopulations in the context of neurotrauma, as well as identify their regulators. Therefore, this review will discuss the major and most recent advances in this field of research, with a primary emphasis on neuroprotection. This review will also discuss the major pitfalls present in the field, with a particular focus on model species and their impact on the development of novel therapies.