Astrocytes play a critical role in neurodegenerative diseases through their heterogeneity, functional specialization, and context-dependent responses. Selective vulnerability in neurodegenerative disorders involves specific brain regions and cell populations, with astrocytes contributing to this vulnerability through maladaptive phenotypic changes. Astrocytes, like neurons, are heterogeneous and respond to diverse signals, integrating inputs to influence brain function. In disease, astrocytes undergo context-dependent changes that promote pathogenic trajectories and functional outcomes. These changes may lead to selective vulnerability by impairing specific brain regions and functions. Astrocytes are essential for brain function and may contribute to pathogenic cascades in disease. Recent studies highlight the role of astrocytes in selective vulnerability, emphasizing their dynamic responses and context-specific contributions. Astrocytes integrate diverse cues and have diverse features and functions, regulating synaptic and neural circuit functions, other glial cells, vascular elements, and homeostatic processes. Astrocytes are heterogeneous and have region-specific morphological and molecular signatures, as well as region- and context-specific calcium dynamics and neurotransmitter release properties. Astrocytes regulate diverse neuronal functions, such as synaptic strength, inhibition, and sensory transmission. Astrocytic alterations and contributions to pathogenic processes are selective and context-dependent, with astrocytes differentially affected by disease-associated factors and pathological processes. Astrocytes can modulate proteinopathy and its effects on brain function, with impaired clearance of protein aggregates contributing to disease progression. Astrocytic metabolic pathways are also involved in neurodegenerative disorders, with changes in metabolic functions affecting neuronal energy supply and metabolic stress. Astrocytes are involved in synaptic transmission and plasticity, regulating neurotransmitter synthesis and cycling, and alterations in these mechanisms have profound effects on neuronal function and vulnerability to disease. Astrocytes also maintain synaptic structure and density through the release of synaptogenic factors and active elimination of synapses. Astrocytic context-dependent roles in disease may inform therapeutic approaches, with targeting of astrocytic functions linked to specific neuronal circuits most susceptible to impairment. Future studies should investigate the roles of circuit-specific and molecularly defined subpopulations of astrocytes, take advantage of advanced genetically encoded indicators and actuators, and rigorously compare astrocytic features and functions across different biological and pathogenic contexts.Astrocytes play a critical role in neurodegenerative diseases through their heterogeneity, functional specialization, and context-dependent responses. Selective vulnerability in neurodegenerative disorders involves specific brain regions and cell populations, with astrocytes contributing to this vulnerability through maladaptive phenotypic changes. Astrocytes, like neurons, are heterogeneous and respond to diverse signals, integrating inputs to influence brain function. In disease, astrocytes undergo context-dependent changes that promote pathogenic trajectories and functional outcomes. These changes may lead to selective vulnerability by impairing specific brain regions and functions. Astrocytes are essential for brain function and may contribute to pathogenic cascades in disease. Recent studies highlight the role of astrocytes in selective vulnerability, emphasizing their dynamic responses and context-specific contributions. Astrocytes integrate diverse cues and have diverse features and functions, regulating synaptic and neural circuit functions, other glial cells, vascular elements, and homeostatic processes. Astrocytes are heterogeneous and have region-specific morphological and molecular signatures, as well as region- and context-specific calcium dynamics and neurotransmitter release properties. Astrocytes regulate diverse neuronal functions, such as synaptic strength, inhibition, and sensory transmission. Astrocytic alterations and contributions to pathogenic processes are selective and context-dependent, with astrocytes differentially affected by disease-associated factors and pathological processes. Astrocytes can modulate proteinopathy and its effects on brain function, with impaired clearance of protein aggregates contributing to disease progression. Astrocytic metabolic pathways are also involved in neurodegenerative disorders, with changes in metabolic functions affecting neuronal energy supply and metabolic stress. Astrocytes are involved in synaptic transmission and plasticity, regulating neurotransmitter synthesis and cycling, and alterations in these mechanisms have profound effects on neuronal function and vulnerability to disease. Astrocytes also maintain synaptic structure and density through the release of synaptogenic factors and active elimination of synapses. Astrocytic context-dependent roles in disease may inform therapeutic approaches, with targeting of astrocytic functions linked to specific neuronal circuits most susceptible to impairment. Future studies should investigate the roles of circuit-specific and molecularly defined subpopulations of astrocytes, take advantage of advanced genetically encoded indicators and actuators, and rigorously compare astrocytic features and functions across different biological and pathogenic contexts.