Abstract: Astrocytes are a major glial cell type in the central nervous system, and they provide trophic and metabolic support to neurons. In addition to these roles, they play crucial roles in modulating synaptic functions, development, and pruning (Brandebura et al., 2023). Astrocytes become reactive (activated) by undergoing morphological, molecular, and functional alterations in response to neuropathology such as in injuries and neurodegenerative diseases (NDs) (Escartin et al., 2021). The pathological significance of reactive astrocytes has been implicated in the onset and progression of NDs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy body disease, and Huntington’s disease. Heterogeneous responses of astrocytes have been seen to exert detrimental and/or beneficial effects on the brain depending on the stimuli. For example, astrocytes have been reported to initiate inflammation and inhibit axon regeneration or withstand neuronal insults and improve recovery (Brandebura et al., 2023). Reactive astrocytes can mitigate disease outcomes by releasing molecules that promote cell repair or exacerbate disease outcomes by releasing molecules that promote the formation of glial scars to prevent axonal regeneration or cause cell death (Brandebura et al., 2023). Therefore, it is critical to understand the molecular mechanisms that regulate the inherent cellular contribution of astrocytes to neuronal degeneration and how they can be manipulated to prevent degeneration or even facilitate neuronal regeneration in NDs. In this perspective, we discuss recent findings on the complexities in the heterogeneous response of astrocytes in NDs. We also emphasize that understanding astrocyte subtypes and their transcriptional profiles in different brain regions and different disease conditions is crucial for the development of effective therapies.